MAO-B inhibitors useful for treating obesity

ABSTRACT

The invention provides novel compounds of formulae I and II:  
                 
that are monoamine oxidase-B inhibitors, which can be useful in treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional Application No. 60/686,585 filed Jun. 2, 2005, now pending, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides relates to compounds and pharmaceutical compositions thereof and methods of using the same for treating obesity. More particularly, the present invention relates to a novel method for treating obesity using an MAO-B inhibitor.

BACKGROUND OF THE INVENTION

L-Selegiline is a monoamine oxidase (MAO) inhibitor that was developed for the treatment of neurological disorders and is primarily used to treat Parkinson's disease. MAO is an enzyme responsible for metabolizing biogenic monoamines including serotonin, dopamine, histamine, and phenylethylamine. By inhibiting MAO located in the central nervous system (CNS), MAO inhibitors and their analogues increase the concentration of monoamines present within the brain synapses. This enhances monoamine-mediated neurotransmission, effectively treating neurological disorders such as Parkinson's disease and depression.

MAO enzymes are also located in a number of peripheral (non-CNS) tissues, including adipocytes, the cells that comprise body fat. The function of MAO enzymes in adipocytes has not been established. Currently, the only approved clinical use of L-selegiline and other MAO inhibitors is for the treatment of neurological disorders such as Parkinson's disease and depression.

Obesity is associated with an increase in the overall amount of adipose tissue (i.e., body fat), especially adipose tissue localized in the abdominal area. Obesity has reached epidemic proportions in the United States. The prevalence of obesity has steadily increased over the years among all racial and ethnic groups. According to the United States Surgeon General, 61% of the adult population and 14% of children are obese or overweight. Forty four million Americans are obese, with an additional eighty million deemed medically overweight. Obesity is responsible for more than 300,000 deaths annually, and will soon overtake tobacco usage as the primary cause of preventable death in the United States. Obesity is a chronic disease that contributes directly to numerous dangerous co-morbidities, including type 2 diabetes, cardiovascular disease, inflammatory diseases, premature aging, and some forms of cancer. Type 2 diabetes, a serious and life-threatening disorder with growing prevalence in both adult and childhood populations, is currently the 7^(th) leading cause of death in the United States. Since more than 80% of patients with type 2 diabetes are overweight, obesity is the greatest risk factor for developing type 2 diabetes. Increasing clinical evidence indicates that the best way to control type 2 diabetes is to reduce weight.

The most popular over-the counter drugs for the treatment of obesity, phenylpropanolamine and ephedrine, and the most popular prescription drug, fenfluramine, were removed from the marketplace as a result of safety concerns. Drugs currently approved for the long-term treatment of obesity fall into two categories: (a) Central Nervous System (CNS) appetite suppressants such as sibutramine and (b) gut lipase inhibitors such as orlistat. CNS appetite suppressants reduce eating behavior through activation of the ‘satiety center’ in the brain and/or by inhibition of the ‘hunger center’ in the brain. Gut lipase inhibitors reduce the absorption of dietary fat from the gastrointestinal (GI) tract. Although sibutramine and orlistat work through very different mechanisms, they share in common the same overall goal of reducing body weight secondary to reducing the amount of calories that reach the systemic circulation. Unfortunately, these indirect therapies produce only a modest initial weight loss (approximately 5% compared to approximately 2% with placebo) that is usually not maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most approved anti-obesity therapeutics produce undesirable and often dangerous side effects that can complicate treatment and interfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiraling obesity epidemic, positions the ‘treatment of obesity’ as one of the largest and most urgent unmet medical needs. There is, therefore, a real and continuing need for the development of improved medications that treat or prevent obesity.

General MAO-B inhibitors such as selegiline have been clinically useful in the treatment of CNS disorders. They have now unexpectedly been discovered to also have anti-obesity activity. Even more surprising is that the anti-obesity activity mediated by these agents is outside of the CNS. This new discovery provides a novel approach for the prevention or treatment of obesity. Moreover, if the CNS effects of these compounds can be eliminated, their peripherally mediated anti-obesity properties should provide therapeutic agents with greater safety. It has, as a result, become highly desirable to find MAO-B inhibitors with limited or no CNS effects. Compounds of this sort are expected to be useful in treating obesity and the variety of co-morbidities to which it contributes.

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novel MAO-B inhibitors or pharmaceutically acceptable salts that are useful to treat obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).

In another aspect, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides novel methods for treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance), comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides novel methods for treating CNS disorders, comprising: administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides processes for preparing novel compounds.

In another aspect, the present invention provides novel compounds or pharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of obesity, diabetes, and/or cardiometabolic disorders.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed compounds or pharmaceutically acceptable salt forms thereof are expected to be effective MAO-B inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the unexpected finding that an MAO-B inhibitor is capable of reducing the amount of adipose tissue (i.e., body fat) in a warm-blooded mammal. This finding was unexpected because body fat can be reduced despite little, if any, concomitant reduction in food intake.

In an embodiment, the present invention provides novel compound A or a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein: Q, R, R¹, W, X, X¹, X², and X³ are all independently selected from H and a group capable of reducing or limiting the CNS activity of compound A; and,

provided that at least one of Q, R, R¹, W, X, X¹, X², and X³ is other than H.

[1] In another embodiment, the present invention provides a novel compound of formula I or II, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(m)CO₂R, C₂₋₆ alkenyl-CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, and, (CH₂)_(n)PO(OR)₂;

A⁻ is a counter ion;

V is selected from O⁻, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

X, X¹, X², and X³ are independently selected from H, OR, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, N(R)₂, (CH₂)_(m)-tetrazole, (CH₂)_(n)CO₂R, (CH₂)_(n)CONR₂, (CH₂)_(n)CN, O(CH₂)_(n)CN, O(CH₂)_(n)-tetrazole, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)PO(OR)₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)CON(R)₂, NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)SO₂OR, NR(CH₂)_(n)-tetrazole, SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, CH₂-aryl, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃A⁻, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n) heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴ and tetrazole is substituted with 0-1 R;

X⁴ is selected from H, OR, O—C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl;

Q is selected from H, OH, C₁₋₆ alkoxy, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₆ alkenyl, O—C₂₋₆ alkenyl-CO₂R, OCH₂CH₂CONRCH₂CO₂R, OCH₂CHMCONRCH₂CO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂CH(NHAc)CO₂R, OCH₂CH(NHR)CO₂R, O(CH₂)_(n)-aryl, and O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

W is selected from H, CO₂R, CON(R)₂, CH₂OH, CH₂OC₁₋₆ alkyl, CH₂OC₂₋₆ alkenyl, CH₂O(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)CON(R)₂, CH₂O—C₂₋₆ alkenyl-CO₂R, CH₂OCH₂CH₂CONRCH₂CO₂R, CH₂OCH₂CHMCONRCH₂CO₂R, CH₂O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)SO₂OR, CH₂OCH₂CH(NHAc)CO₂R, CH₂OCH₂CH(NHR)CO₂R, CH₂O—C₂₋₆ alkenyl, and CH₂O(CH₂)_(n)CONH₂, CH₂O(CH₂)_(n)-aryl, and CH₂O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein heteroaryl is substituted with 1-2 X⁴;

M is independently selected from H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, (CH₂)_(n)-aryl, heteroaryl, and (CH₂)_(n)-heteroaryl, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

m is independently selected from 0, 1, 2, 3, and 4; and,

n is independently selected from 1, 2, 3, and 4;

provided that at least one of X, X¹, X², and X³ is other than H, alkyl, alkoxy, hydroxyl, and halo.

In another variant, the compounds of the present invention have no more than one acid functionality.

[2] In another embodiment, the present invention provides a novel compound of formula I₁ or II₁, or a stereoisomer or pharmaceutically acceptable salt thereof:

[3] In another embodiment, the present invention provides a novel compound of formula Ia, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

X and X¹ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, and NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

X⁴ is selected from H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl;

n is independently selected from 1, 2, and 3;

provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[3a] In another embodiment, the present invention provides a novel compound of formula Ia, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

one of X and X¹ is H and the other is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, and NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[4] In another embodiment, the present invention provides a novel compound of formula Ia₁, or a stereoisomer or pharmaceutically acceptable salt thereof:

[5] In another embodiment, the present invention provides a novel compound of formula Ib, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(m)CO₂R, C₂₋₄ alkenyl-CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, and, (CH₂)_(n)PO(OR)₂;

X and X¹ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

X⁴ is selected from H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl;

W is selected from H, CH₂OH, CH₂OC₁₋₄ alkyl, CH₂OC₂₋₄ alkenyl, CH₂O(CH₂)_(n)CO₂R, CH₂O—C₂₋₄ alkenyl-CO₂R, CH₂O(CH₂)_(n)CON(R)₂, CH₂O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)-aryl, and CH₂O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

m is independently selected from 0, 1, and 2; and,

n is independently selected from 1, 2, and 3;

provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[5a] In another embodiment, the present invention provides a novel compound of formula Ib, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

one of X and X¹ is H and the other is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[6] In another embodiment, the present invention provides a novel compound of formula Ib₁, or a stereoisomer or pharmaceutically acceptable salt thereof:

[7] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹ is selected from H and C₁₋₄ alkyl;

X, X¹, X², and X³ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, N(R)₂, (CH₂)_(m)-tetrazole, (CH₂)_(n)CO₂R, (CH₂)_(n)CONR₂, (CH₂)_(n)CN, O(CH₂)_(n)CN, O(CH₂)_(n)-tetrazole, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)PO(OR)₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)CON(R)₂, NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)SO₂OR, NR(CH₂)_(n)-tetrazole, SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, CH₂-aryl, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃A⁻, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴ and tetrazole is substituted with 0-1 R;

X⁴ is selected from H, OR, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl;

A⁻ is selected from Cl and Br;

M is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, heteroaryl, and (CH₂)_(n)-heteroaryl, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and,

m is independently selected from 0, 1, and 2; and,

n is independently selected from 1, 2, and 3;

provided that at least one of X, X¹, X², and X³ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[7a] In another embodiment, the present invention provides a novel compound of formula Ic, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

three of X, X¹, X², and X³ are H and the fourth is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, C₁₋₄ alkoxy, —CN, N(R)₂, (CH₂)_(m)-tetrazole, (CH₂)_(n)CO₂R, (CH₂)_(n)CONR₂, (CH₂)_(n)CN, O(CH₂)_(n)CN, O(CH₂)_(n)-tetrazole, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)PO(OR)₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)CON(R)₂, NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)SO₂OR, NR(CH₂)_(n)-tetrazole, SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, CH₂-aryl, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃A⁻, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴ and tetrazole is substituted with 0-1 R;

provided that at least one of X, X¹, X², and X³ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[8] In another embodiment, the present invention provides a novel compound of formula Ic₁ or a pharmaceutically acceptable salt thereof:

[9] In another embodiment, the present invention provides a novel compound of formula Id, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(m)CO₂R, (CH₂)_(n)PO(OR)₂, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

X, X¹, and X² are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

X⁴ is selected from H, OH, C₁₋₆ alkoxy C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl;

Q is selected from OH, C₁₋₄ alkoxy, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, O—C₂₋₄ alkenyl-CO₂R, OCH₂CH₂CONRCH₂CO₂R, OCH₂CHMCONRCH₂CO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂CH(NHAc)CO₂R, OCH₂CH(NHR)CO₂R, O(CH₂)_(n)-aryl, and O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S;

M is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, heteroaryl, and (CH₂)_(n)-heteroaryl, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and,

m is independently selected from 0, 1, and 2; and,

n is independently selected from 1, 2, and 3;

provided that at least one of X, X¹, and X² is other than H, alkyl, alkoxy, hydroxyl, and halo.

[9a] In another embodiment, the present invention provides a novel compound of formula Id, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

two of X, X¹, and X² are H and the third is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

provided that at least one of X, X¹, and X² is other than H, alkyl, alkoxy, hydroxyl, and halo.

[10] In another embodiment, the present invention provides a novel compound of formula Id₁, or a stereoisomer or pharmaceutically acceptable salt thereof:

[11] In another embodiment, the present invention provides a novel compound of formula IIa or a stereoisomer thereof:

wherein:

R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R¹ is selected from H and C₁₋₄ alkyl;

A⁻ is selected from Cl⁻ and Br⁻;

V is selected from O⁻, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

X and X¹ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, NRSO₂CH₃, SO₂NRCH₃, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

X⁴ is selected from H, OR, C₁₋₆ alkoxy C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl;

n is independently selected from 1, 2, and 3;

provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[11a] In another embodiment, the present invention provides a novel compound of formula IIa or a stereoisomer thereof, wherein:

one of X and X¹ is H and the other is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, NRSO₂CH₃, SO₂NRCH₃, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴;

provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.

[12] In another embodiment, the present invention provides a novel compound of formula Ia₁:

In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating a disease, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.

In another embodiment, the cardiometabolic disorder is selected from hypertension, dyslipidemias (e.g., undesirable blood lipid levels, elevated cholesterol levels, and lowered LDL levels), high blood pressure, and insulin resistance.

In another embodiment, the present invention provides a novel method for treating a co-morbidity of obesity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating a co-morbidity of obesity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease.

In another embodiment, the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder.

In another embodiment, the present invention provides a novel method for treating a CNS disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the CNS disorder is selected from acute and chronic neurological disorders, cognitive disorders, and memory deficits. Examples of these disorders include chronic or traumatic degenerative processes of the nervous system, which include Alzheimer's disease, other types of dementia, minimal cognitive impairment, and Parkinson's disease. Other examples of CNS disorders include psychiatric diseases, which include depression, anxiety, panic attack, social phobia, schizophrenia, and anorexia. Further examples of CNS disorders include withdrawal syndromes induced by alcohol, nicotine and other addictive drugs. Additional examples of CNS disorders include neuropathic pain and neuroinflamatory diseases (e.g., multiple sclerosis).

In another embodiment, the present invention also provides a method of preventing or reversing the deposition of adipose tissue in a mammal by the administration of a MAO-B inhibitor. By preventing or reversing the deposition of adipose tissue, MAO-B inhibitors are expected to reduce the incidence or severity of obesity, thereby reducing the incidence or severity of associated co-morbidities.

In another embodiment, the present invention provides a compound of the present invention for use in therapy.

In another embodiment, the present invention provides the use of the present invention for the manufacture of a medicament for the treatment of obesity, diabetes, cardiometabolic disorders, and a combination thereof.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

Definitions

The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.

The compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries. Geometric isomers of olefins, C═N double bonds, or other types of double bonds may be present in the compounds described herein, and all such stable isomers are included in the present invention. Specifically, cis and trans geometric isomers of the compounds of the present invention may also exist and may be isolated as a mixture of isomers or as separated isomeric forms. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.

“Alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C₁₋₆ alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, and C₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆ alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in a saturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Alkoxy” represents an alkyl group as defined above with the indicated number of hydrocarbon atoms attached through an oxygen bridge. C₁₋₆ alkoxy, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species, such as chloride, bromide, hydroxide, acetate, and sulfate.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 membered monocyclic, bicyclic, or tricyclic ring, wherein at least one ring, if more than one is present, is aromatic. Examples of aryl include fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl group is bicyclic or tricyclic, then at least one of the two or three rings must contain a heteroatom, though both or all three may each contain one or more heteroatoms. If the heteroaryl group is bicyclic or tricyclic, then only one of the rings must be aromatic. The N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited. The nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroaryl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preventing the deposition of adipose tissue covers methods of treating wherein the levels of adipose tissue of a subject remain about the same as prior to being treated in accordance with the present invention (i.e., its pre-administration level) or not more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% greater than pre-administration level (particularly when the subject is pre-disposed to increasing adipose tissue levels).

Reversing the deposition of adipose tissue covers methods of treating wherein the levels of adipose tissue of a subject are lower than those prior to being treated in accordance with the present invention (i.e., its pre-administration level). Examples of lower include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% or more lower than pre-administration level.

Mammal and patient covers warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, bovine, and human and (b) human.

“Treating” or “treatment” covers the treatment of a disease-state in a mammal, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, e.g., arresting it development; and/or (c) relieving the disease-state, e.g., causing regression of the disease state until a desired endpoint is reached. Treating also includes the amelioration of a symptom of a disease (e.g., lessen the pain or discomfort), wherein such amelioration may or may not be directly affecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p 1445, the disclosure of which is hereby incorporated by reference.

“Therapeutically effective amount” includes an amount of a compound of the present invention that is effective when administered alone or in combination to treat obesity or another indication listed herein. “Therapeutically effective amount” also includes an amount of the combination of compounds claimed that is effective to treat the desired indication. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased effect, or some other beneficial effect of the combination compared with the individual components.

Utility

Obesity is defined as having a body mass index (BMI) of 30 or above. The index is a measure of an individual's body weight relative to height. BMI is calculated by dividing body weight (in kilograms) by height (in meters) squared. Normal and healthy body weight is defined as having a BMI between 20 and 24.9. Overweight is defined as having a BMI of 25 or above. Obesity has reached epidemic proportions in the U.S., with 44 million obese Americans, and an additional eighty million deemed medically overweight.

Obesity is a disease characterized as a condition resulting from the excess accumulation of adipose tissue, especially adipose tissue localized in the abdominal area. It is desirable to treat overweight or obese patients by reducing their amount of adipose tissue, and thereby reducing their overall body weight to within the normal range for their sex and height. In this way, their risk for co-morbidities such as diabetes and cardiovascular disease will be reduced. It is also desirable to prevent normal weight individuals from accumulating additional, excess adipose tissue, effectively maintaining their body weights at a BMI <25, and preventing the development of co-morbidities. It is also desirable to control obesity, effectively preventing overweight and obese individuals from accumulating additional, excess adipose tissue, reducing the risk of further exacerbating their co-morbidities.

There exist two forms of MAO, designated MAO-A and MAO-B. The two forms differ with respect to substrate and inhibitor specificities and amino acid number and sequence. A preferred substrate for MAO-B is beta-phenylethylamine. In contrast, a preferred substrate for MAO-A is serotonin. Some MAO inhibitors show selectivity for MAO-A or for MAO-B, whereas other MAO inhibitors show little, if any selectivity. For example, the MAO inhibitor clorgyline preferentially inhibits MAO-A; the MAO inhibitor L-selegiline preferentially inhibits MAO-B; and, the MAO inhibitor iproniazid is non-selective (i.e., has a similar affinity for both). Examples of selectivity include a compound having about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more fold higher affinity for one form of MAO than for the other form. One of ordinary skill in the art recognizes that there can be some difficulty in classifying MAO inhibitors. Some compounds may selectively inhibit one form of MAO in vitro and then lose their selectivity in vivo. Also, selectivity of a compound may vary from species to species or from tissue to tissue. In the context of the present invention, it is desirable to inhibit MAO-B activity in vivo in a mammal. Thus, selectivity and affinity are based on the in vivo activity of the MAO inhibitor and the mammalian species to which it is being or to be administered. Examples of the selectivity of a MAO-B inhibitor of the present invention include (a) at least a 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, to 100-fold greater affinity for MAO-B than MAO-A in the mammalian species (e.g., human) to be treated and (b) at least 100-fold greater affinity for MAO-B than MAO-A in the mammalian species (e.g., human) to be treated.

Some of the compounds of the present invention have been designed to have reduced CNS exposure by virtue of their inability or limited ability to penetrate the blood-brain barrier (e.g., quaternary salts or acid substituents) or by their participation in active transport systems, thus reducing centrally mediated side-effects, a potential problem with many anti-obesity agents.

Other compounds of the present invention are expected to penetrate the blood-brain barrier and therefore be useful to treat CNS disorders (e.g., Parkinson's disease, depression, and Alzheimer's disease).

MAO enzymes are also located in a number of peripheral (non-CNS) tissues, including adipocytes; the cells that comprise body fat. In order to treat non-CNS disorders (e.g., obesity, diabetes, and/or cardiometabolic disorders), it is necessary to administer enough of a drug sufficient to inhibit MAO in peripheral tissues. MAO inhibitors in use today to treat various psychiatric and neurological diseases, regardless of route of administration, enter the CNS from the systemic circulation. While present in the systemic circulation, such drugs have access to peripheral tissues, including adipose tissue, liver, and muscle. One of skill in the art recognizes that MAO inhibitors intended to enter the CNS from the systemic circulation in order to treat psychiatric and neurological diseases also have access to MAO in peripheral tissues, including adipose tissue, liver, and muscle. Thus, an MAO inhibitor useful for treating non-CNS disorders may have some access to the CNS from the systemic circulation.

Drugs enter the CNS from the systemic circulation by crossing the blood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’ that protects the brain by preventing the entry of many potentially harmful substances into the CNS from the systemic circulation. Much is known about the BBB, and of the physical-chemical properties required for compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readily eliminated through transport mechanisms (J Clin Invest. 97, 2517(1996)) are known in the literature and have low CNS activity due to their inability to develop brain levels necessary for pharmacological action. The BBB has at least one mechanism to remove drugs prior to their accumulation in the CNS. P-Glycoproteins (P-gp) localized in plasma membrane of the BBB can influence the brain penetration and pharmacological activity of many drugs through translocation across membranes. The lack of accumulation into the brain by some drugs can be explained by their active removal from the brain by P-gp residing in the BBB. For example, the typical opioid drug loperamide, clinically used as an antidiarrheal, is actively removed from the brain by P-gp, thus explaining its lack of opiate-like CNS effects. Another example is domperidone, a dopamine receptor blocker that participates in the P-gp transport (J Clin Invest. 97, 2517(1996)). Whereas dopamine receptor blockers that cross the BBB can be used to treat schizophrenia, the readily-eliminated domperidone can be used to prevent emesis, without the likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structural characteristics that retard or prevent BBB penetration or contribute to participation in active elimination processes have been identified in various classes of therapeutics. These include antihistamines (Drug Metab. Dispos. 31, 312 (2003)), beta-adrenergic receptor antagonists (B-blockers)(Eur. J. Clin. Pharmacol. 28, Suppl: 21-3 (1985); Br. J. Clin. Pharmacol., 11 (6), 549-553 (1981)), non-nucleoside reverse transcriptase inhibitors (NNRTIs)(J. Pharm Sci., 88(10) 950-954 (1999)), and opioid antagonists. This latter group has been tested in relation to their activity in the GI tract. These peripherally selective opioid antagonists are described in various US patents as being useful in the treatment of non-CNS pathologies in mammals, in particular those of the GI tract (see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238).

Other types of non-brain penetrant compounds can be prepared through the creation of a charge within the molecule. Thus, the addition of a methyl group to the tertiary amine functionality of the drugs scopolamine or atropine, unlike the parent molecules, prevents their passage across the BBB through the presence of a positive charge. However, the new molecules (methyl-scopolamine and methyl-atropine) retain their full anticholinergic pharmacological properties. As such, these drugs can also be used to treat peripheral diseases, without the concern of adverse CNS effects. The quaternary ammonium compound methylnaltrexone is also used for the prevention and/or treatment of opioid and non-opioid induced side effects associated with opioid administration.

MAO-B inhibitors such as selegiline have been useful in the treatment of CNS disorders. The unexpected discovery that the anti-obesity activity mediated by these agents is mediated by a non-CNS mechanism may make it desirable that the compounds of the present invention be peripherally restricted, i.e., have an inability or limited ability to cross the BBB or be readily eliminated from the brain through active transport systems, when a non-CNS disorder is to be treated. It may be desirable for the compounds of the present invention to be peripherally restricted, which in turn will result in no or very limited CNS effects. Compounds that provide peripherally mediated anti-obesity properties should result in therapeutic agents with greater safety, as previously demonstrated in earlier classes of peripherally restricted agents. It can be desirable that the compounds of the present invention, when administered in a therapeutically effective amount, have no or very limited CNS effects. It can also be desirable that the lack of CNS effects is a result of the compounds of the present invention having minimal brain concentrations when administered in therapeutically effective amounts. In this context, minimal brain concentrations means levels that are too low to be therapeutically effective for the treatment of a CNS indication or too low to cause significant or measurable deleterious or undesired side effects. It is noted that CNS activity is desirable when seeking to treat a CNS disorder.

Compound A is Rasagiline when Q, R, R¹, W, X, X¹, X², and X³ are all H. Rasagiline is a drug that crosses the BBB and is indicated fro Parkinson's disease. In compound A, one of R, R¹, R², X, X¹, Y, and Z is a group capable of reducing or limiting the CNS activity of compound A. This reducing or limiting occurs via at least one of R, R¹, R², X, X¹, Y, and Z being a group the either limits compound A's ability to cross the BBB relative to that of Rasagiline or enables it to be actively removed at a level that is higher than Rasagiline's. Examples of brain levels of compound A include levels that are (a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than Rasagiline, when administered at the same dosage; (b) from 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than Rasagiline, when administered at the same dosage; and, (c) from 98, 99, to 100% lower than Rasagiline, when administered at the same dosage.

Most methods of treating obesity are dependent on a significant reduction in energy intake, either by a decrease in food intake (e.g., sibutramine) or by inhibition of fat absorption (e.g., orlistat). In the present invention, it can be desirable for adipose tissue to be significantly reduced in the absence of a significant reduction in food intake. The weight loss, as a result of the present invention, comes from the treatment with an MAO-B inhibitor, largely independent of appetite and food intake. Examples of the level of food intake during adipose tissue loss include (a) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) food intake is maintained, increased, or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below its pre-administration level; (c) food intake is maintained, increased or about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below its pre-administration level; and (d) food intake level is maintained, increased or about 0, 1, 2, 3, 4, or 5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by a concomitant loss of lean muscle mass. This is particularly evident in cancer patients who show a wasting of all body tissue components, including adipose tissue and lean muscle mass. In the present invention, however, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in lean body mass. Adipose tissue loss comes from treatment with an MAO-B inhibitor, independent of a significant change in lean body mass. Examples of the level of lean body mass during adipose tissue loss include (a) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) lean body mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.

In some cases, loss of adipose tissue can be accompanied by a concomitant loss of water mass. This is particularly evident with diet regimens that promote dehydration. In the present invention, it can be desirable for body fat to be significantly reduced in the absence of a significant reduction in water mass. In other words, adipose tissue loss comes from treatment with an MAO-B inhibitor, independent of a significant change in water mass. Examples of the level of water mass during adipose tissue loss include (a) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level); (b) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels; (c) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d) water mass is maintained, increased, or is no more than about 1, 2, 3, 4, or 5% below pre-administration levels.

Sibutramine and orlistat are currently marketed for use in the treatment of obesity. These two compounds achieve weight loss through entirely different mechanisms. Sibutramine, a CNS appetite suppressant, inhibits the neuronal reuptake of serotonin and noradrenaline. Orlistat inhibits gut lipase enzymes that are responsible for breaking down ingested fat.

The mechanism of action of MAO-B inhibitors is believed to be entirely different from appetite suppressants, gut lipase inhibitors, and other agents with similar indications (e.g., serotonin agonists, leptin, fatty acid synthase inhibitors, monoamine oxidase (MAO) inhibitors). Co-administration of a MAO-B inhibitor together with one or more other agents that are useful for treating the indications described above (e.g., obesity, diabetes, cardiometabolic disorders, and a combination thereof) is expected to be beneficial, by producing, for example, either additive or synergistic effects. Examples of additional agents include an appetite suppressant and a lipase inhibitor. Therefore, the present invention provides a method of treating obesity, diabetes, and/or cardiometabolic disorders, comprising administering a therapeutically effective amount of a compound of the present invention and a second component selected from an appetite suppressant (e.g., sibutramine, phentermine, fenfluramine) and a gut lipase inhibitor (e.g., orlistat).

MAO-B inhibitors are expected to promote weight loss without appreciably reducing caloric intake. Co-administration of an MAO-B inhibitor together with an appetite suppressant is expected to produce either additive or synergistic effects on weight loss. Similarly, co-administration of an MAO-B inhibitor together with a lipase inhibitor is expected to produce either additive or synergistic effects on weight loss.

The ability of compounds to inhibit MAOs can be determined using the method of R. Uebelhack et al., Pharmacopsychiatry 31, 1988, p 187-192 (as described below).

Preparation of platelet-rich plasma and platelets. Venous blood from healthy subjects was collected between 8 and 8.30 a.m. after an overnight fast into EDTA-containing vacutainer tubes (11.6 mg EDTA/ml blood). After centrifugation of the blood at 250×g for 15 minutes at 20° C., the supernatant platelet-rich plasma (PRP) was collected and the number of platelets in PRP counted with a cell counter (MOIAB, Hilden, Germany). 2 ml of PRP was spun at 1500×g for 10 min to yield a platelet pellet. The pellet was washed three times with ice-cold saline, resuspended in 2 ml Soerensen phoshate buffer, pH 7.4 and stored at −18° C. for one day.

MAO assay. Fresh PRP or frozen platelet suspension (100 μL) was generally preincubated for 10 min in the absence or presence of drugs at 37° C. in 100 uL of 0.9% NaCl solution or phosphate buffer pH 7.4, respectively, at 37° C. 50 μL of 2-phenylethylamine-[ethyl-1-14C]hydrochloride (P EA) solution (specific activity 56 Ci/mol, Amersham) was then added in a final concentration of 5 μM, and the incubation was continued for 30 min. The reaction was terminated by the addition of 50 μL of 4M HClO₄. The reaction product of MAO, phenylacetaldehyde, was extracted into 2 mL of n-hexane. An aliquot of the organic phase was added to scintillator cocktail and the radioactivity was determined using a liquid scintillation counter. Product formation was linear with time for at least 60 min with appropriate platelet numbers. Blank values were obtained by including 2 mM pargyline in the incubation mixtures. All assays were performed in duplicate.

The ability of compounds to inhibit MAO activity can also be determined using the following method. cDNA's encoding human MAO-B can be transiently transfected into EBNA cells using the procedure described by E.-J. Schlaeger and K. Christensen (Transient Gene Expression in Mammalian Cells Grown in Serum-free Suspension Culture; Cytotechnology, 15: 1-13, 1998). After transfection, cells are homogeneized by means of a Polytron homogeneiser in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM phenylmethanesulfonyl fluoride. Cell membranes are obtained by centrifugation at 45,000×g and, after two rinsing steps with 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes are eventually re-suspended in buffer and aliquots stored at −80° C. until use.

MAO-B enzymatic activity can be assayed using a spectrophotometric assay adapted from the method described by M. Zhou and N. Panchuk-Voloshina (A One-Step Fluorometric Method for the Continuous Measurement of Monoamine Oxidase Activity, Analytical Biochemistry, 253: 169-174, 1997). Briefly, membrane aliquots are incubated in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37° C. with or without various concentrations of the compounds. After incubation, the enzymatic reaction is started by the addition of the MAO substrate tyramine together with 1 U/ml horse-radish peroxidase (Roche Biochemicals) and 80 μM N-acetyl-3,7,-dihydroxyphenoxazine (Amplex Red, Molecular Probes). The samples are further incubated for 30 min at 37° C. in a final volume of 200 μl and absorbance is determined at a wavelength of 570 nm using a SpectraMax plate reader (Molecular Devices). Background (non-specific) absorbance is determined in the presence of 10 μM L-deprenyl for MAO-B. IC₅₀ values are determined from inhibition curves obtained using nine inhibitor concentrations in duplicate, by fitting data to a four parameter logistic equation.

Compounds of the present invention are expected to be MAO-B inhibitors. Representative compounds have been tested, as measured in the assay described herein, and have been shown to be active as their IC₅₀ values were found to be in the range of ≦10 μM. Compounds of the present invention are considered to be MAO-B inhibitors if they have an IC₅₀ value less than or equal to 10 μM. Additional examples of desirable activity levels of MAO-B inhibitors useful in the present invention include (a) an IC₅₀ value of 1 μM or lower, (b) an IC₅₀ value of 0.1 μM or lower, (c) an IC₅₀ value of 0.01 μM or lower, (d) an IC₅₀ value of 0.001 μM or lower, and (e) an IC₅₀ value of 0.0001 μM or lower.

In the present invention, MAO-B inhibitor(s) can be administered enterally, parenterally, orally, and transdermally. One skilled in this art is aware that the routes of administering the compounds of the present invention may vary significantly. In addition to other oral administrations, sustained release compositions may be favored. Other examples of routes include injections (e.g., intravenous, intramuscular, and intraperitoneal); subcutaneous; subdermal implants; buccal, sublingual, topical, rectal, vaginal, and intranasal administrations. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable systems of administration may also be used.

If a solid composition in the form of tablets is prepared, the main active ingredient can be mixed with a pharmaceutical vehicle, examples of which include silica, starch, lactose, magnesium stearate, and talc. The tablets can be coated with sucrose or another appropriate substance or they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active ingredient continuously. Gelatin capsules can be obtained by mixing the active ingredient with a diluent and incorporating the resulting mixture into soft or hard gelatin capsules. A syrup or elixir can contain the active ingredient in conjunction with a sweetener, which is preferably calorie-free, an antiseptic (e.g., methylparaben and/or propylparaben), a flavoring, and an appropriate color. Water-dispersible powders or granules can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors. Rectal administration can be effected using suppositories, which are prepared with binders melting at the rectal temperature (e.g., cocoa butter and/or polyethylene glycols). Parenteral administration can be effected using aqueous suspensions, isotonic saline solutions, or injectable sterile solutions, which contain pharmacologically compatible dispersants and/or wetting agents (e.g., propylene glycol and/or polyethylene glycol). The active ingredient can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives. The active ingredient can also be presented in the form of a complex with a cyclodextrin, for example α-, β-, or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.

The dose of the MAO-B inhibitor administered daily will vary on an individual basis and to some extent may be determined by the severity of the disease being treated (e.g., obesity). The dose of the MAO-B inhibitor will also vary depending on the MAO-B inhibitor administered. A example of a range of dosages of an MAO-B inhibitor is about from 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100 mg/kg of mammal body weight. The MAO-B inhibitor can be administered in a single dose or in a number of smaller doses over a period of time. The length of time during which the MAO-B inhibitor is administered varies on an individual basis, and can continue until the desired results are achieved (i.e., reduction of body fat, or prevention of a gain in body fat). Therapy could, therefore, last from 1 day to weeks, months, or even years depending upon the subject being treated, the desired results, and how quickly the subject responds to treatment in accordance with the present invention.

A possible example of a tablet of the present invention is as follows. Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows. Ingredient mg/Tablet Active ingredient 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

In the above capsule, the active ingredient has a suitable particle size. The crystalline lactose and the microcrystalline cellulose are homogeneously mixed with one another, sieved, and thereafter the talc and magnesium stearate are admixed. The final mixture is filled into hard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention is as follows. Ingredient mg/Tablet Active substance 1.0 mg 1 N HCl 20.0 μl acetic acid 0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1 N NaOH q.s. ad pH 5 H₂O q.s. ad 1 mL Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

In Scheme 1, the keto acid can be esterified using methanol and sulfuric acid (step a), and subsequent treatment with propargylamine and sodium cyanoborohydride in slightly acidic media should provide the propargylamino ester (step b). The corresponding acid can be produced by treatment with lithium hydroxide in aqueous solution containing a co-solvent (step c). Alternatively, the amino ester can be further alkylated with methyl bromide to give the tertary-amino ester (step d), and subsequent lithium hydroxide treatment should give tertiary amino acid (step e).

As shown in Scheme 2, hydroxyindanone can be benzylated using one equivalent of sodium hydride and benzyl bromide at low temperature in a solvent such as DMF or THF to give the benzyloxyindanone (step a). Treatment of the ketone with propargylamine and sodium cyanoborohydride in the presence of acetic acid in dichloroethane should provide the secondary amine (step b). Protection of the secondary amine with trityl chloride in pyridine solution should give the tritylated secondary amine (step c). Deprotonation of the protected propargylamine using n-butyl lithium followed by treatment with ethyl bromoacetate should produce the ester (step d). Treatment with dry hydrogen bromide in acetic acid should cause a loss of the trityl protecting group to give benzyloxy aminoester (step e), and subsequent exposure to trifluoroacetic acid should provide.hydroxyindanylamino ester (step f). Lithium hydroxide treatment should give the secondary amino acid (step g). Alternatively, the benzyloxy-indane amino ester of step e can also be hydrolyzed, as above, to give the benzyloxy-indane amino acid which may optionally have halogen, CF₃, alkyl or alkoxy substituents on the phenyl ring.

As shown in Scheme 2′, hydroxyindanone can be benzylated with a variety of benzyl bromides that are optionally substituted with various groups (e.g., ester, alkylester, oxyalkylester nitrile, alkylnitrile, oxyalkylnitrile, halogen, CF₃, etc.) in acetone at about 60° C. in the presence of potassium carbonate to give the substituted benzyloxyindanones (step a). In the case of substituents on the phenyl group that are nitrites, treatment of these ketones with propargylamine and sodium cyanoborohydride in acetonitrile and acetic acid at about 30° C. should provide the secondary amine (step b). Hydration of these nitrites using 30% hydrogen peroxide in DMSO in the presence of potassium carbonate at about room temperature should yield the carboxamides (step c). Alternatively, the nitrites can be converted to tetrazoles by treatment with sodium azide and trioctyltin chloride in xylenes at reflux, followed by cleavage of the trialkylstannyl adduct with anhydrous HCl in toluene/THF solution (step f). In the case of indanones having benzyl groups with ester substituents, reductive amination with propargyl amine in acetonitrile and acetic acid at 30-50° C. can afford the amino esters (step d). Hydrolysis of the esters using lithium hydroxide in aqueous THF can produce the acids (step e). Halogen, alkyl, alkoxy and CF3-substituted benzyloxy indanes can be produced from the indanones via reductive amination as described above.

Scheme 3 describes how indanylpropargylamine (rasagiline) can be protected with trityl chloride to give the tritylated secondary amine (step a). Treatment with n-butyl lithium followed by methyl chloroformate should give the trityl-protected amino ester (step b), which can be de-protected with hydrogen bromide in acetic acid (step c). The corresponding acid can be produced by treatment with aqueous lithium hydroxide solution (step d).

As illustrated in Scheme 4, a keto acid can be esterified using methanol and sulfuric acid (step a), and subsequent treatment with propargylamine and sodium cyanoborohydride in slightly acidic media should provide the propargylamino ester (step b). The secondary amine can be protected with trityl chloride or other suitable protecting groups to give the protected ester (step c). The ester can then be reduced with lithium aluminum hydride to give the primary alcohol (step d), which upon deprotonation with sodium hydride and alkylation with ethyl bromopropionate should provide the ester (step e). Removal of the protecting group using hydrogen bromide in acetic acid or other suitable deprotecting reagents should afford the secondary amino ester (step f), and hydrolysis of the ester with lithium hydroxide in aqueous solution should yield the amino acid (step g).

As depicted in Scheme 5, a keto acid can be esterified using methanol and sulfuric acid (step a), and subsequent treatment with propargylamine and sodium cyanoborohydride in slightly acidic media should provide the propargylamino ester (step b). The secondary amine can be protected with trityl chloride or other suitable protecting groups to give the protected ester (step c). The ester can then be reduced with lithium aluminum hydride to give the primary alcohol (step d) which upon deprotonation with sodium hydride and alkylation with methyl bromide should provide the ether (step e). Treatment of the methyl ether with n-butyl lithium followed by alkylation with ethyl iodoacetaate should provide the ester (step f). Subsequent deprotection of the amine using hydrogen bromide in acetic acid or other suitable deprotecting reagents (step g), and subsequent hydrolysis of the ester with lithium hydroxide in aqueous solution will produce the amino acid ether (step h).

Scheme 6 shows alkylation of the hydroxyindanone using potassium carbonate in acetone using ethyl bromoacetate at about room temperature or above can give the indanone ester (step a). Treatment of the keto-ester with propargylamine and sodium cyanoborohydride in acetonitrile in the presence of acetic acid at about 30° C. can provide the secondary amine (step b). Hydrolysis of the ester using lithium hydroxide in aqueous solution should afford the amino acid (step c). Alternatively, the ester can be alkylated with formalin and sodium triacetoxyborohydride in dichloroethane in the presence of acetic acid to give the N-methyl analog which can be hydrolyzed to the acid as described above. Alkylation of the indanone with bromoacetonitrile in acetone in the presence of potassium carbonate at about room temperature or above can produce the keto-nitrile (step d). Treatment of the keto-nitrile with propargylamine and sodium cyanoborohydride in acetonitrile in the presence of acetic acid at about 30° C. should afford the secondary amine (step e). Subsequent hydration of the nitrile with 30% hydrogen peroxide in DMSO in the presence of potassium carbonate can provide the carboxamide (step f).

As shown in Scheme 7, an aminoalcohol can be treated with STABASE (1,1,4,4-tetramethydisilylaza-yclopentane), aryl aldehydes, or other suitable protecting agents to give a protected amino alcohol (step a). The alcohol can then be deprotonated with sodium hydride and alkylated with ethyl bromobutyrate to give the ester (step b). Removal of the protecting group using tosyl acid in methanol (STABASE) or other suitable conditions for other protecting groups should afford the primary amino ester after neutralization (step c). Treatment of this amine with propioaldehyde diethyl acetal and sodium cyanoborohydride under slightly acidic moist conditions should produce the propargyl aminoester (step d). Further alkylation of this amine using formalin and sodium cyanoborohydride can provide the methylated teriaryamino ester (step e). Subsequent treatment of the secondary (step f) or the tertiary (step g) amino esters with lithium hydroxide in aqueous solution should yield the secondary and tertiary amino acids, respectively.

Scheme 8 shows how tertiary-amino indanes, where Z can be H or O(CH₂)_(n)-phenyl and the phenyl can be optionally substituted with halogen or CF₃, when treated with an alkyl halides, such as methyl bromide or methyl iodide, in a solvent such as toluene, ethanol or ether can give the corresponding quaternary ammonium salts (step a). Treatment of these tertiary amines with Davis reagent (phenyloxaziridinebenezene-sulfonamide) in methylene chloride at room temperature can give the corresponding amine N-oxides (step b).

One stereoisomer of a compound of the present invention may be a more potent MAO-B inhibitor than its counterpart(s). Thus, stereoisomers are included in the present invention. Some of these stereoisomers are shown below in Schemes 9-13. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as described in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 or using enantiomerically pure acids and bases. A chiral compound of the present invention may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Tables A-C below describe examples of the present invention that have been synthesized and tested. The activities of the compounds are as follows:

+=an IC50 of ≦10 μM;

++=IC50 of ≦1 μM; and,

++=an IC50≦100 nM.

The examples can be prepared according to the methods of the scheme numbers provided for each example. TABLE A

All compounds racemic Num- Re- NMR Synthesis ber X R sults (CDCl₃-ppm) Route 1 CH₂C₆H₅ H + ring-CH: 1.93(m) Scheme 2 C≡CH: 2.27(m) ring-CH: 2.41(m) ring-CH: 2.85(m) ring-CH: 3.05(m) N—CH₂: 3.53(m) N—CH: 4.48(t) PhCH₂O: 5.09 aromatic H's 6.70—7.35 2 CH₂CH₂C₆H₅ H +++ ring-CH: 1.93(m) Scheme 2 C≡CH: 2.26(m) ring-CH: 2.38(m) ring-CH: 2.78(m) ring-CH: 2.98(m) PhOCH₂: 3.09 (t) N—CH₂: 3.51(q) PhOCH₂: 4.18 (t) N—CH: 4.44(t) aromatic H's 6.78—7.50 3 CH₂CO₂Et CH₃ + ester-CH₃: 1.30(t) Scheme 6 ring-CH₂: 2.17(m) C≡CH: 2.26(m) ring-CH: 2.87(m) ring-CH: 3.00(m) N—CH₂: 3.35(dq) ester-CH₂: 4.26(q) N—CH: 4.52(t) PhOCH₂: 4.64 aromatic H's 6.61—7.26 4 CH₂CO₂Et H + ester-CH₃: 1.29(t) Scheme 6 ring-CH: 1.88(m) C≡CH: 2.26(m) ring-CH: 2.41(m) ring-CH: 2.86(m) ring-CH: 3.05(m) N—CH₂: 3.52(q) ester-CH₂: 4.26(q) N—CH: 4.43(t) PhOCH₂: 4.63 aromatic H's 6.61—7.18

TABLE B

All compounds racemic Re- NMR Syn- Num- sults (CDCl₃) thesis ber X R (B) ppm Route 5 CH₂C₆H₅ H +++ ring-CH: 2.03(m) Scheme 2 C≡CH: 2.30(m) ring-CH: 2.39(m) ring-CH: 2.80(m) ring-CH: 3.08(m) N—CH₂: 3.52(m) N—CH: 4.43(m) PhCH₂O: 5.04 aromatic H's 6.82—7.42 6 CH₂CH₂C₆H₅ H +++ ring-CH: 2.04(m) Scheme 2 C≡CH: 2.32(m) ring-CH: 2.37(m) ring-CH: 2.79(m) ring-CH: 3.09(m) PhCH2: 3.10(t) N—CH₂: 3.52(m) N—CH: 4.47(m) PhOCH₂: 4.15(t) aromatic H's 6.73—7.26 7 CH₂C₆H₅ CH₃ +++ ring-CH₂: 2.18(m) Scheme 2 C≡CH: 2.30(m) N—CH₃: 2.38(s) ring-CH: 2.80(m) ring-CH: 2.99(m) N—CH₂: 3.39(q) N—CH: 4.44(m) PhCH₂O: 5.05(s) aromatic H's 6.84-7.50 8 CH₂CO₂Et H + (CDCl₃) Scheme 6 ester-CH₃: 1.27(t) ring-CH: 1.89(m) C≡CH: 2.25(m) ring-CH: 2.38(m) ring-CH: 2.80(m) ring-CH: 3.00(m) N—CH₂: 3.49(m) ester-CH₂: 4.27(q) N—CH: 4.38(m) EtO₂CCH₂O: 4.60(s) aromatic H's 6.73—7.26 9 CH₂CO₂Et CH₃ ++ (CDCl₃) Scheme 6 ester-CH₃: 1.29(t) ring-CH₂: 2.12(m) C≡CH: 2.24(m) N—CH_(3:): 2.32(s) ring-CH: 2.78(m) ring-CH: 2.95(m) N—CH₂: 3.32(q) ester-CH₂: 4.27(q) N—CH: 4.38(t) EtO₂CCH₂O: 4.60(s) aromatic H's 6.76—7.31 10 CH₂CO₂H CH₃ + (CD₃OD) Scheme 6 ring-CH₂: 2.50(m) N—CH₃: 2.77(s) ring-CH: 3.00(m) ring-CH: 3.17(m) C≡CH: 3.38(m) N—CH₂: 4.05(dq) HO₂CCH₂O: 4.70(s) N—CH: 5.09(dd) aromatic H's 6.92-6.51 11 (CH₂)₄CO₂Et H + (CDCl₃) Scheme 6 ester-CH₃: 1.26(t) ring-CH₂: 1.92(m) C≡CH: 2.27(m) N—CH₃: 2.36(s) ring-CH: 2.81(m) ring-CH: 3.05(m) N—CH₂: 3.50(s) OCH₂: 3.95(q) ester-CH₂: 4.13(q) N—CH: 4.38(t) aromatic H's 6.72-7.26 12 CH₂CH═CHCO₂Et CH₃ +++ (CDCl₃) Scheme 6 ester-CH₃: 1.29(t) ring-CH₂: 2.24(m) C≡CH: 2.36(m) N—CH₃: 2.44(s) ring-CH: 2.83(m) ring-CH: 3.06(m) N—CH₂: 3.46(br m) ester-CH₂: 4.22(q) N—CH: 4.52(m) OCH₂-vinyl: 4.69(q) CH═: 6.19 (2 t) CH═: 7.06 (2 t) aromatic H's 6.78-7.45 13 CH₂CH═CHCO₂Et H ++ (CDCl₃) Scheme 6 ester-CH₃: 1.30(t) ring-CH: 1.93 (m) C≡CH: 2.29(m) ring-CH: 2.40 (m) ring-CH: 2.82(m) ring-CH: 3.09(m) N—CH₂: 3.51(q) ester-CH₂: 4.21(q) N—CH: 4.41(t) OCH₂-vinyl: 4.68(q) CH═: 6.19 (dt) CH═: 7.07 (dt) aromatic H's 6.74-7.3 14 CH₂C₆H₅CO₂Me(4) CH₃ ++ (CDCl₃) Scheme 2′ ring-CH₂: 2.14(m) C≡CH: 2.25(m) N—CH₃: 2.33(s) ring-CH 2.78(m) ring-CH: 2.96(m) N—CH₂: 3.33(dq) OCH₃: 3.92(s) N—CH: 4.39(t) PhCH₂O: 5.11(q) aromatic H's 6.8-8.1 15 CH₂C₆H₅CO₂Me(4) H + (CDCl₃) Scheme 2′ ring-CH: 1.94(m) ring-CH: 2.39(m) C≡CH: 2.28(m) ring-CH: 2.80(m) ring-CH: 3.06(m) N—CH₂: 3.50(s) OCH₃: 3.92(s) N—CH: 4.40(t) PhCH₂O: 5.10(s) aromatic H's 6.8-8.1 16 CH₂C₆H₅CONH₂(4) H ++ (CD₃OD) Scheme 2′ ring-CH: 1.92(m) ring-CH: 2.35(m) C≡CH: 2.67(m) ring-CH: 2.81(m) ring-CH: 3.02(m) N—CH₂: 3.46(q) N—CH: 4.38(t) PhCH₂O: 5.15(s) aromatic H's 6.8-7.9 17 CH₂C₆H₅CO₂Me(3) CH₃ ++ (CDCl₃) Scheme 2′ ring-CH₂: 2.14(m) C≡CH: 2.25(m) ring-CH: 2.78(m) ring-CH: 2.94(m) N—CH₂: 3.33(q) OCH₃: 3.93(s) N—CH: 4.39(t) PhCH₂O: 5.09(s) aromatic H's 6.8-8.15 18 CH₂C₆H₅CO₂Me(3) H +++ (CDCl₃) Scheme 2′ ring-CH: 1.89(m) C≡CH: 2.26(m) ring-CH: 2.38(m) ring-CH: 2.80(m) ring-CH: 3.01(m) N—CH₂: 3.50(q) OCH₃: 3.93(s) N—CH: 4.37(t) PhCH₂O: 5.09(s) aromatic H's 6.8-8.13 19 CH₂C₆H₅CO₂H(3) H + (CD₃OD) Scheme 2′ ring-CH: 2.08(m) ring-CH: 2.45(m) ring-CH: 2.90(m) C≡CH: 2.94(m) ring-CH: 3.10(m) N—CH₂: 3.69(s) N—CH: 4.59(q) PhCH₂O: 5.14(s) aromatic H's 6.9-8.10 20 CH₂C₆H₅CONH₂(3) H +++ (CD₃OD) Scheme 2′ ring-CH₂: 2.15(m) C≡CH: 2.69(m) N—CH₃: 2.33(s) ring-CH: 2.78(m) ring-CH: 2.95(m) N—CH₂: 3.31(s) OCH₃: 3.92(s) N—CH: 4.39(t) PhCH₂O: 5.12(s) aromatic H's 6.85-8.0 21 CH₂C₆H₅CH₂CO₂Me(4) H ++ (CDCl₃) Scheme 2′ ring-CH: 1.89(m) ring-CH: 2.37(m) ring-CH: 2.79(m) C≡CH: 2.27(m) ring-CH: 3.02(m) N—CH₂: 3.50(q) PhCH₂CO: 3.65 (s) OCH₃: 3.70 (s) N—CH: 4.37(q) PhCH₂O: 5.13(s) aromatic H's 6.8-7.45 22 CH₂C₆H₅CH₂CO₂H(4) H ˜+ (CD₃OD) Scheme 2′ ring-CH: 1.90(m) ring-CH: 2.37(m) ring-CH: 2.80(m) C≡CH: 2.27(m) ring-CH: 3.02(m) N—CH₂: 3.48(q) PhCH₂O: 3.31 (s) N—CH: 4.37(q) PhCH₂O: 5.03(s) aromatic H's 6.8-7.35 23 CH₂C₆H₅OCH₂CO₂Et(4) H + (CDCl₃) Scheme 2′ ester-CH₃: 1.30(t) ring-CH: 1.89(m) C≡CH: 2.26(m) ring-CH: 2.38(m) ring-CH: 2.78(m) ring-CH: 3.02(m) N—CH₂: 3.51(q) ester-CH₂: 4.28(q) N—CH: 4.37(t) OCH₂CO: 4.63(s) PhCH₂O: 4.97(s) aromatic H's 6.80-7.37 24 CH₂C₆H₅OCH₂CO H ++ (CD₃OD) Scheme 2′ NH₂(4) ring-CH: 1.90(m) ring-CH: 2.36(m) C≡CH: 2.68(m) ring-CH: 2.78(m) ring-CH: 3.05(m) N—CH₂: 3.45(q) OCH₂CO: 4.50(s) N—CH: 4.37(q) PhCH₂O: 4.99(s) aromatic H's 6.8-7.45 25 CH₂C₄H₂O—CO₂Me(2,5) H + (CDCl₃) Scheme 2′ (furan) ring-CH: 1.89(m) C≡CH: 2.26(m) ring-CH: 2.39(m) ring-CH: 2.80(m) ring-CH: 3.00(m) N—CH₂: 3.50(q) O—CH₃: 3.90(s) N—CH: 4.37(t) OCH₂CO: 4.63(s) furan-CH₂O: 5.05(s) furan H's 6.51(d), 6.80(d) phenyl H's 6.78-7.26 26 CH₂CH₂CH₂PO(OEt)₂ H + (CD₃OD) Scheme 6 ester-CH₃: 1.32(t) ring-CH: 1.98(m) chain-CH₂'s: 2.00(m) ring-CH: 2.38(m) C≡CH: 2.75(m) ring-CH: 2.83(m) ring-CH: 3.05(m) N—CH₂: 3.52(q) ester-CH₂ 4.10(m) O—CH₂ 4.02(t) N—CH: 4.43(q) aromatic H's 6.8-7.45

TABLE C

All compounds racemic Num- Re- NMR Synthesis ber X R sults (CDCl₃-ppm) Route 27 CH₂C₆H₅ H + ring-CH: 1.90(m) Scheme 2 C≡CH: 2.24(m) ring-CH: 2.41(m) ring-CH: 2.76(m) ring-CH: 2.97 (m) N—CH₂: 3.51(s) N—CH: 4.40(m) PhCH₂O: 5.06 aromatic H's 6.87-7.45 28 CH₂C₆H₅ CH₃ + ring-CH₂: 2.13(m) Scheme 2 C≡CH: 2.26(m) N—CH₃: 2.34(s) ring-CH: 2.41(m) ring-CH: 2.76(m) ring-CH: 2.97 (m) N—CH₂: 3.51(s) N—CH: 4.46(m) PhCH₂O: 5.06 aromatic H's 6.86-7.50 29 CH₂CH₂C₆H₅ H + ring-CH: 1.92(m) Scheme 2 C≡CH: 2.27(m) ring-CH: 2.41(m) ring-CH: 2.75(m) ring-CH: 3.00(m) PhOCH₂: 3.10 (t) N—CH₂: 3.52(q) PhOCH₂: 4.19(t) N—CH: 4.41(t) aromatic H's 6.77-7.37 30 CH₂CO₂Et CH₃ + ester-CH₃: 1.30(t) Scheme 6 ring-CH₂: 2.13(m) C≡CH: 2.26(m) N—CH₃: 2.32(s) ring-CH: 2.74(m) ring-CH: 2.89(m) N—CH₂: 3.51(s) ester-CH₂: 4.27(q) N—CH: 4.43(m) aromatic H's 6.81-7.28 31 CH₂CH═CHCO₂Et CH₃ ++ ester-CH₃: 1.30(t) Scheme 6 ring-CH₂: 2.16(m) C≡CH: 2.29(m) N—CH₃: 2.37(s) ring-CH: 2.77(m) ring-CH: 2.90(m) N—CH₂: 3.37(m) ester-CH₂: 4.20(q) N—CH: 4.48(m) OCH₂-vinyl: 4.70(m) CH═: 6.19 (dt) CH═: 7.07 (dt) aromatic H's 6.80-7.15 32 CH₂CH≡CHCO₂Et H + ester-CH₃: 1.30(t) Scheme 6 ring-CH: 1.95(m) C≡CH: 2.32(m) ring-CH: 2.44(m) ring-CH: 2.78(m) ring-CH: 3.00(m) N—CH₂: 3.54(m) ester-CH₂: 4.21(q) N—CH: 4.45(m) OCH₂-vinyl: 4.70(m) CH═: 6.19 (dt) CH═: 7.07 (dt) aromatic H's 6.80-7.2 33 CH₂C₆H₅CO₂Me(4) CH₃ + ring-CH₂: Scheme 2′ 2.15(m) C≡CH: 2.27(m) N—CH₃: 2.35(s) ring-CH: 2.75(m) ring-CH: 2.89(m) N—CH₂: 3.35(m) OCH₃: 3.92(s) N—CH: 4.45(m) PhOCH₂: 5.13(q) aromatic H's 6.86-8.05 34 CH₂C₆H₅CO₂Me(4) H + ring-CH: Scheme 2′ 1.95(m) C≡CH: 2.26(m) ring-CH: 2.43(m) ring-CH: 2.77(m) ring-CH: 2.95(m) N—CH₂: 3.51(q) OCH₃: 3.92(s) N—CH: 4.38(m) PhOCH₂: 5.12(s) aromatic H's 6.83-8.10 35 CH₂C₆H₅CO₂Me(3) H + ring-CH: Scheme 2′ 1.93(m) C≡CH: 2.29(m) ring-CH: 2.42(m) ring-CH: 2.77(m) ring-CH: 2.97(m) N—CH₂: 3.51(q) OCH₃: 3.93(s) N—CH: 4.42(t) PhOCH₂: 5.10(s) aromatic H's 6.85-8.15 36 CH₂C₆H₅O H ++ (CDCl₃) Scheme 2′ CH₂CN(3) ring-CH: 1.87(m) C≡CH: 2.27(m) ring-CH: 2.43(m) ring-CH: 2.77(m) ring-CH: 2.95(m) N—CH₂: 3.50(q) N—CH: 4.37(t) O—CH₂CN: 4.78(s) PhCH₂O: 5.06(s) aromatic H's 6.83-7.38 37 CH₂C₆H₅CN(3) H + (CDCl₃) Scheme 2′ ring-CH: 1.87(m) C≡CH: 2.28(m) ring-CH: 2.44(m) ring-CH: 2.78(m) ring-CH: 2.95(m) N—CH₂: 3.51(q) N—CH: 4.38(t) PhCH₂O: 5.08(s) aromatic H's 6.82-7.73 38 CH₂C₆H₅CONH₂(3) H + (CD₃OD) Scheme 2′ ring-CH: 1.88(m) ring-CH: 2.37(m) C≡CH: 2.67(m) ring-CH: 2.75(m) ring-CH: 2.94(m) N—CH₂: 3.43(q) N—CH: 4.38(t) PhCH₂O: 5.13(s) aromatic H's 6.86-7.97

Tables I-VI show representative examples of the compounds of the present invention. Each example in each table represents an individual species of the present invention. TABLE I

Ex. # X X¹ R R¹ 1 H H CH₃ H 2 H H H H 3 H H CH₃ CH₃ 4 H H H CH₃ 5 OH H CH₃ H 6 OH H H H 7 OH H CH₃ CH₃ 8 OH H H CH₃ 9 H OH CH₃ H 10 H OH H H 11 H OH CH₃ CH₃ 12 H OH H CH₃ 13 OCH₃ H CH₃ H 14 OCH₃ H H H 15 OCH₃ H CH₃ CH₃ 16 OCH₃ H H CH₃ 17 H OCH₃ CH₃ H 18 H OCH₃ H H 19 H OCH₃ CH₃ CH₃ 20 H OCH₃ H CH₃ 21 OCH₂C₆H₅ H CH₃ H 22 OCH₂C₆H₅ H H H 23 OCH₂C₆H₅ H CH₃ CH₃ 24 OCH₂C₆H₅ H H CH₃ 25 H OCH₂C₆H₅ CH₃ H 26 H OCH₂C₆H₅ H H 27 H OCH₂C₆H₅ CH₃ CH₃ 28 H OCH₂C₆H₅ H CH₃ 29 OCH₂C₆H₅ H CH₃ H 30 OCH₂C₆H₅ H H H 31 OCH₂C₆H₅ H CH₃ CH₃ 32 OCH₂C₆H₅ H H CH₃ 33 OCH₂CH₂C₆H₅ H CH₃ H 34 OCH₂CH₂C₆H₅ H H H 35 OCH₂CH₂C₆H₅ H CH₃ CH₃ 36 OCH₂CH₂C₆H₅ H H CH₃ 37 H OCH₂CH₂C₆H₅ CH₃ H 38 H OCH₂CH₂C₆H₅ H H 39 H OCH₂CH₂C₆H₅ CH₃ CH₃ 40 H OCH₂CH₂C₆H₅ H CH₃ 41 OCH₂CH═CH₂ H CH₃ H 42 OCH₂CH═CH₂ H H H 43 OCH₂CH═CH₂ H CH₃ CH₃ 44 OCH₂CH═CH₂ H H CH₃ 45 H OCH₂CH═CH₂ CH₃ H 46 H OCH₂CH═CH₂ H H 47 H OCH₂CH═CH₂ CH₃ CH₃ 48 H OCH₂CH═CH₂ H CH₃ 49 OCH₂CONH₂ H CH₃ H 50 OCH₂CONH₂ H H H 51 OCH₂CONH₂ H CH₃ CH₃ 52 OCH₂CONH₂ H H CH₃ 53 H OCH₂CONH₂ CH₃ H 54 H OCH₂CONH₂ H H 55 H OCH₂CONH₂ CH₃ CH₃ 56 H OCH₂CONH₂ H CH₃ 57 Br H CH₃ H 58 Br H H H 59 Br H CH₃ CH₃ 60 Br H H CH₃ 61 H Cl CH₃ H 62 H Cl H H 63 H Cl CH₃ CH₃ 64 H Cl H CH₃ 65 NO₂ H CH₃ H 66 NO₂ H H H 67 NO₂ H CH₃ CH₃ 68 NO₂ H H CH₃ 69 NH₂ H CH₃ H 70 NH₂ H H H 71 NH₂ H CH₃ CH₃ 72 NH₂ H H CH₃ 73 NHSO₂CH₃ H CH₃ H 74 NHSO₂CH₃ H H H 75 NHSO₂CH₃ H CH₃ CH₃ 76 NHSO₂CH₃ H H CH₃ 77 H CH₃ CH₃ H 78 H CH₃ H H 79 H CH₃ CH₃ CH₃ 80 H CH₃ H CH₃

TABLE IIa

Ex. # X X¹ R¹ 1. H H CO₂CH₂CH₃ 2. H H CO₂H 3. OH H CO₂CH₂CH₃ 4. OH H CO₂H 5. OCH₃ H CO₂CH₂CH₃ 6. OCH₃ H CO₂H 7. OCH₂CH═CH₂ H CO₂CH₂CH₃ 8. OCH₂CH═CH₂ H CO₂H 9. OCH₂C₆H₅ H CO₂CH₂CH₃ 10. OCH₂C₆H₅ H CO₂H 11. OCH₂CH₂C₆H₅ H CO₂CH₂CH₃ 12. OCH₂CH₂C₆H₅ H CO₂H 13. OCH₂CONH₂ H CO₂CH₂CH₃ 14. OCH₂CONH₂ H CO₂H 15. H Cl CO₂CH₂CH₃ 16. H Cl CO₂H 17. Br H CO₂CH₂CH₃ 18. Br H CO₂H 19. H CH₃ CO₂CH₂CH₃ 20. H CH₃ CO₂H 21. NO₂ H CO₂CH₂CH₃ 22. NO₂ H CO₂H 23. NH₂ H CO₂CH₂CH₃ 24. NH₂ H CO₂H 25. NHSO₂CH₃ H CO₂CH₂CH₃ 26. NHSO₂CH₃ H CO₂H 27. H OH CO₂CH₂CH₃ 28. H OH CO₂H 29. H OCH₃ CO₂CH₂CH₃ 30. H OCH₃ CO₂H 31. H OCH₂CH═CH₂ CO₂CH₂CH₃ 32. H OCH₂CH═CH₂ CO₂H 33. H OCH₂C₆H₅ CO₂CH₂CH₃ 34. H OCH₂C₆H₅ CO₂H 35. H OCH₂CH₂C₆H₅ CO₂CH₂CH₃ 36. H OCH₂CH₂C₆H₅ CO₂H 37. H OCH₂CONH₂ CO₂CH₂CH₃ 38. H OCH₂CONH₂ CO₂H 39. H H CH₂CO₂CH₂CH₃ 40. H H CH₂CO₂H 41. OH H CH₂CO₂CH₂CH₃ 42. OH H CH₂CO₂H 43. OCH₃ H CH₂CO₂CH₂CH₃ 44. OCH₃ H CH₂CO₂H 45. OCH₂CH═CH₂ H CH₂CO₂CH₂CH₃ 46. OCH₂CH═CH₂ H CH₂CO₂H 47. OCH₂C₆H₅ H CH₂CO₂CH₂CH₃ 48. OCH₂C₆H₅ H CH₂CO₂H 49. OCH₂CH₂C₆H₅ H CH₂CO₂CH₂CH₃ 50. OCH₂CH₂C₆H₅ H CH₂CO₂H 51. OCH₂CONH₂ H CH₂CO₂CH₂CH₃ 52. OCH₂CONH₂ H CH₂CO₂H 53. H Cl CH₂CO₂CH₂CH₃ 54. H Cl CH₂CO₂H 55. Br H CH₂CO₂CH₂CH₃ 56. Br H CH₂CO₂H 57. H CH₃ CH₂CO₂CH₂CH₃ 58. H CH₃ CH₂CO₂H 59. NO₂ H CH₂CO₂CH₂CH₃ 60. NO₂ H CH₂CO₂H 61. NH₂ H CH₂CO₂CH₂CH₃ 62. NH₂ H CH₂CO₂H 63. NHSO₂CH₃ H CH₂CO₂CH₂CH₃ 64. NHSO₂CH₃ H CH₂CO₂H 65. H OH CH₂CO₂CH₂CH₃ 66. H OH CH₂CO₂H 67. H OCH₃ CH₂CO₂CH₂CH₃ 68. H OCH₃ CH₂CO₂H 69. H OCH₂CH═CH₂ CH₂CO₂CH₂CH₃ 70. H OCH₂CH═CH₂ CH₂CO₂H 71. H OCH₂C₆H₅ CH₂CO₂CH₂CH₃ 72. H OCH₂C₆H₅ CH₂CO₂H 73. H OCH₂CH₂C₆H₅ CH₂CO₂CH₂CH₃ 74. H OCH₂CH₂C₆H₅ CH₂CO₂H 75. H OCH₂CONH₂ CH₂CO₂CH₂CH₃ 76. H OCH₂CONH₂ CH₂CO₂H 77. H H CH₂CH₂CO₂CH₂CH₃ 78. H H CH₂CH₂CO₂H 79. OH H CH₂CO₂CH₂CH₂CH₃ 80. OH H CH₂CH₂CO₂H 81. OCH₃ H CH₂CH₂CO₂CH₂CH₃ 82. OCH₃ H CH₂CH₂CO₂H 83. OCH₂CH═CH₂ H CH₂CO₂CH₂CH₂CH₃ 84. OCH₂CH═CH₂ H CH₂CH₂CO₂H 85. OCH₂C₆H₅ H CH₂CH₂CO₂CH₂CH₃ 86. OCH₂C₆H₅ H CH₂CH₂CO₂H 87. OCH₂CH₂C₆H₅ H CH₂CO₂CH₂CH₂CH₃ 88. OCH₂CH₂C₆H₅ H CH₂CH₂CO₂H 89. OCH₂CONH₂ H CH₂CH₂CO₂CH₂CH₃ 90. OCH₂CONH₂ H CH₂CH₂CO₂H 91. H Cl CH₂CO₂CH₂CH₂CH₃ 92. H Cl CH₂CH₂CO₂H 93. Br H CH₂CH₂CO₂CH₂CH₃ 94. Br H CH₂CH₂CO₂H 95. H CH₃ CH₂CO₂CH₂CH₂CH₃ 96. H CH₃ CH₂CH₂CO₂H 97. NO₂ H CH₂CH₂CO₂CH₂CH₃ 98. NO₂ H CH₂CH₂CO₂H 99. NH₂ H CH₂CO₂CH₂CH₂CH₃ 100. NH₂ H CH₂CH₂CO₂H 101. NHSO₂CH₃ H CH₂CH₂CO₂CH₂CH₃ 102. NHSO₂CH₃ H CH₂CH₂CO₂H 103. H OH CH₂CO₂CH₂CH₂CH₃ 104. H OH CH₂CH₂CO₂H 105. H OCH₃ CH₂CH₂CO₂CH₂CH₃ 106. H OCH₃ CH₂CH₂CO₂H 107. H OCH₂CH═CH₂ CH₂CO₂CH₂CH₂CH₃ 108. H OCH₂CH═CH₂ CH₂CH₂CO₂H 109. H OCH₂C₆H₅ CH₂CH₂CO₂CH₂CH₃ 110. H OCH₂C₆H₅ CH₂CH₂CO₂H 111. H OCH₂CH₂C₆H₅ CH₂CO₂CH₂CH₂CH₃ 112. H OCH₂CH₂C₆H₅ CH₂CH₂CO₂H 113. H OCH₂CONH₂ CH₂CH₂CO₂CH₂CH₃ 114. H OCH₂CONH₂ CH₂CH₂CO₂H 115. H H CH₂CH₂PO(OCH₂CH₃)₂ 116. H H CH₂CH₂PO(OH)₂ 117. OH H CH₂CH₂PO(OCH₂CH₃)₂ 118. OH H CH₂CH₂PO(OH)₂ 119. OCH₃ H CH₂CH₂PO(OCH₂CH₃)₂ 120. OCH₃ H CH₂CH₂PO(OH)₂ 121. OCH₂CH═CH₂ H CH₂CH₂PO(OCH₂CH₃)₂ 122. OCH₂CH═CH₂ H CH₂CH₂PO(OH)₂ 123. OCH₂C₆H₅ H CH₂CH₂PO(OCH₂CH₃)₂ 124. OCH₂C₆H₅ H CH₂CH₂PO(OH)₂ 125. OCH₂CH₂C₆H₅ H CH₂CH₂PO(OCH₂CH₃)₂ 126. OCH₂CH₂C₆H₅ H CH₂CH₂PO(OH)₂ 127. OCH₂CONH₂ H CH₂CH₂PO(OCH₂CH₃)₂ 128. OCH₂CONH₂ H CH₂CH₂PO(OH)₂ 129. H Cl CH₂CH₂PO(OCH₂CH₃)₂ 130. H Cl CH₂CH₂PO(OH)₂ 131. Br H CH₂CH₂PO(OCH₂CH₃)₂ 132. Br H CH₂CH₂PO(OH)₂ 133. H CH₃ CH₂CH₂PO(OCH₂CH₃)₂ 134. H CH₃ CH₂CH₂PO(OH)₂ 135. NO₂ H CH₂CH₂PO(OCH₂CH₃)₂ 136. NO₂ H CH₂CH₂PO(OH)₂ 137. NH₂ H CH₂CH₂PO(OCH₂CH₃)₂ 138. NH₂ H CH₂CH₂PO(OH)₂ 139. NHSO₂CH₃ H CH₂CH₂PO(OCH₂CH₃)₂ 140. NHSO₂CH₃ H CH₂CH₂PO(OH)₂ 141. H OH CH₂CH₂PO(OCH₂CH₃)₂ 142. H OH CH₂CH₂PO(OH)₂ 143. H OCH₃ CH₂CH₂PO(OCH₂CH₃)₂ 144. H OCH₃ CH₂CH₂PO(OH)₂ 145. H OCH₂CH═CH₂ CH₂CH₂PO(OCH₂CH₃)₂ 146. H OCH₂CH═CH₂ CH₂CH₂PO(OH)₂ 147. H OCH₂C₆H₅ CH₂CH₂PO(OCH₂CH₃)₂ 148. H OCH₂C₆H₅ CH₂CH₂PO(OH)₂ 149. H OCH₂CH₂C₆H₅ CH₂CH₂PO(OCH₂CH₃)₂ 150. H OCH₂CH₂C₆H₅ CH₂CH₂PO(OH)₂ 151. H OCH₂CONH₂ CH₂CH₂PO(OCH₂CH₃)₂ 152. H OCH₂CONH₂ CH₂CH₂PO(OH)₂ 153. H H CH₂CH═CHCO₂CH₂CH₃ 154. H H CH₂CH═CHCO₂H 155. OH H CH₂CH═CHCO₂CH₂CH₃ 156. OH H CH₂CH═CHCO₂H 157. OCH₃ H CH₂CH═CHCO₂CH₂CH₃ 158. OCH₃ H CH₂CH═CHCO₂H 159. OCH₂CH═CH₂ H CH₂CH═CHCO₂CH₂CH₃ 160. OCH₂CH═CH₂ H CH₂CH═CHCO₂H 161. OCH₂C₆H₅ H CH₂CH═CHCO₂CH₂CH₃ 162. OCH₂C₆H₅ H CH₂CH═CHCO₂H 163. OCH₂CH₂C₆H₅ H CH₂CH═CHCO₂CH₂CH₃ 164. OCH₂CH₂C₆H₅ H CH₂CH═CHCO₂H 165. OCH₂CONH₂ H CH₂CH═CHCO₂CH₂CH₃ 166. OCH₂CONH₂ H CH₂CH═CHCO₂H 167. H Cl CH₂CH═CHCO₂CH₂CH₃ 168. H Cl CH₂CH═CHCO₂H 169. Br H CH₂CH═CHCO₂CH₂CH₃ 170. Br H CH₂CH═CHCO₂H 171. H CH₃ CH₂CH═CHCO₂CH₂CH₃ 172. H CH₃ CH₂CH═CHCO₂H 173. NO₂ H CH₂CH═CHCO₂CH₂CH₃ 174. NO₂ H CH₂CH═CHCO₂H 175. NH₂ H CH₂CH═CHCO₂CH₂CH₃ 176. NH₂ H CH₂CH═CHCO₂H 177. NHSO₂CH₃ H CH₂CH═CHCO₂CH₂CH₃ 178. NHSO₂CH₃ H CH₂CH═CHCO₂H 179. H OH CH₂CH═CHCO₂CH₂CH₃ 180. H OH CH₂CH═CHCO₂H 181. H OCH₃ CH₂CH═CHCO₂CH₂CH₃ 182. H OCH₃ CH₂CH═CHCO₂H 183. H OCH₂CH═CH₂ CH₂CH═CHCO₂CH₂CH₃ 184. H OCH₂CH═CH₂ CH₂CH═CHCO₂H 185. H OCH₂C₆H₅ CH₂CH═CHCO₂CH₂CH₃ 186. H OCH₂C₆H₅ CH₂CH═CHCO₂H 187. H OCH₂CH₂C₆H₅ CH₂CH═CHCO₂CH₂CH₃ 188. H OCH₂CH₂C₆H₅ CH₂CH═CHCO₂H 189. H OCH₂CONH₂ CH₂CH═CHCO₂CH₂CH₃ 190. H OCH₂CONH₂ CH₂CH═CHCO₂H

TABLE IIb

Ex. # X X¹ R¹ 1. H H CO₂CH₂CH₃ 2. H H CO₂H 3. OH H CO₂CH₂CH₃ 4. OH H CO₂H 5. OCH₃ H CO₂CH₂CH₃ 6. OCH₃ H CO₂H 7. OCH₂CH═CH₂ H CO₂CH₂CH₃ 8. OCH₂CH═CH₂ H CO₂H 9. OCH₂C₆H₅ H CO₂CH₂CH₃ 10. OCH₂C₆H₅ H CO₂H 11. OCH₂CH₂C₆H₅ H CO₂CH₂CH₃ 12. OCH₂CH₂C₆H₅ H CO₂H 13. OCH₂CONH₂ H CO₂CH₂CH₃ 14. OCH₂CONH₂ H CO₂H 15. H Cl CO₂CH₂CH₃ 16. H Cl CO₂H 17. Br H CO₂CH₂CH₃ 18. Br H CO₂H 19. H CH₃ CO₂CH₂CH₃ 20. H CH₃ CO₂H 21. NO₂ H CO₂CH₂CH₃ 22. NO₂ H CO₂H 23. NH₂ H CO₂CH₂CH₃ 24. NH₂ H CO₂H 25. NHSO₂CH₃ H CO₂CH₂CH₃ 26. NHSO₂CH₃ H CO₂H 27. H OH CO₂CH₂CH₃ 28. H OH CO₂H 29. H OCH₃ CO₂CH₂CH₃ 30. H OCH₃ CO₂H 31. H OCH₂CH═CH₂ CO₂CH₂CH₃ 32. H OCH₂CH═CH₂ CO₂H 33. H OCH₂C₆H₅ CO₂CH₂CH₃ 34. H OCH₂C₆H₅ CO₂H 35. H OCH₂CH₂C₆H₅ CO₂CH₂CH₃ 36. H OCH₂CH₂C₆H₅ CO₂H 37. H OCH₂CONH₂ CO₂CH₂CH₃ 38. H OCH₂CONH₂ CO₂H 39. H H CH₂CO₂CH₂CH₃ 40. H H CH₂CO₂H 41. OH H CH₂CO₂CH₂CH₃ 42. OH H CH₂CO₂H 43. OCH₃ H CH₂CO₂CH₂CH₃ 44. OCH₃ H CH₂CO₂H 45. OCH₂CH═CH₂ H CH₂CO₂CH₂CH₃ 46. OCH₂CH═CH₂ H CH₂CO₂H 47. OCH₂C₆H₅ H CH₂CO₂CH₂CH₃ 48. OCH₂C₆H₅ H CH₂CO₂H 49. OCH₂CH₂C₆H₅ H CH₂CO₂CH₂CH₃ 50. OCH₂CH₂C₆H₅ H CH₂CO₂H 51. OCH₂CONH₂ H CH₂CO₂CH₂CH₃ 52. OCH₂CONH₂ H CH₂CO₂H 53. H Cl CH₂CO₂CH₂CH₃ 54. H Cl CH₂CO₂H 55. Br H CH₂CO₂CH₂CH₃ 56. Br H CH₂CO₂H 57. H CH₃ CH₂CO₂CH₂CH₃ 58. H CH₃ CH₂CO₂H 59. NO₂ H CH₂CO₂CH₂CH₃ 60. NO₂ H CH₂CO₂H 61. NH₂ H CH₂CO₂CH₂CH₃ 62. NH₂ H CH₂CO₂H 63. NHSO₂CH₃ H CH₂CO₂CH₂CH₃ 64. NHSO₂CH₃ H CH₂CO₂H 65. H OH CH₂CO₂CH₂CH₃ 66. H OH CH₂CO₂H 67. H OCH₃ CH₂CO₂CH₂CH₃ 68. H OCH₃ CH₂CO₂H 69. H OCH₂CH═CH₂ CH₂CO₂CH₂CH₃ 70. H OCH₂CH═CH₂ CH₂CO₂H 71. H OCH₂C₆H₅ CH₂CO₂CH₂CH₃ 72. H OCH₂C₆H₅ CH₂CO₂H 73. H OCH₂CH₂C₆H₅ CH₂CO₂CH₂CH₃ 74. H OCH₂CH₂C₆H₅ CH₂CO₂H 75. H OCH₂CONH₂ CH₂CO₂CH₂CH₃ 76. H OCH₂CONH₂ CH₂CO₂H 77. H H CH₂CH₂CO₂CH₂CH₃ 78. H H CH₂CH₂CO₂H 79. OH H CH₂CH₂CO₂CH₂CH₃ 80. OH H CH₂CH₂CO₂H 81. OCH₃ H CH₂CH₂CO₂CH₂CH₃ 82. OCH₃ H CH₂CH₂CO₂H 83. OCH₂CH═CH₂ H CH₂CO₂CH₂CH₂CH₃ 84. OCH₂CH═CH₂ H CH₂CH₂CO₂H 85. OCH₂C₆H₅ H CH₂CH₂CO₂CH₂CH₃ 86. OCH₂C₆H₅ H CH₂CH₂CO₂H 87. OCH₂CH₂C₆H₅ H CH₂CO₂CH₂CH₂CH₃ 88. OCH₂CH₂C₆H₅ H CH₂CH₂CO₂H 89. OCH₂CONH₂ H CH₂CH₂CO₂CH₂CH₃ 90. OCH₂CONH₂ H CH₂CH₂CO₂H 91. H Cl CH₂CO₂CH₂CH₂CH₃ 92. H Cl CH₂CH₂CO₂H 93. Br H CH₂CH₂CO₂CH₂CH₃ 94. Br H CH₂CH₂CO₂H 95. H CH₃ CH₂CO₂CH₂CH₂CH₃ 96. H CH₃ CH₂CH₂CO₂H 97. NO₂ H CH₂CH₂CO₂CH₂CH₃ 98. NO₂ H CH₂CH₂CO₂H 99. NH₂ H CH₂CO₂CH₂CH₂CH₃ 100. NH₂ H CH₂CH₂CO₂H 101. NHSO₂CH₃ H CH₂CH₂CO₂CH₂CH₃ 102. NHSO₂CH₃ H CH₂CH₂CO₂H 103. H OH CH₂CO₂CH₂CH₂CH₃ 104. H OH CH₂CH₂CO₂H 105. H OCH₃ CH₂CH₂CO₂CH₂CH₃ 106. H OCH₃ CH₂CH₂CO₂H 107. H OCH₂CH═CH₂ CH₂CO₂CH₂CH₂CH₃ 108. H OCH₂CH═CH₂ CH₂CH₂CO₂H 109. H OCH₂C₆H₅ CH₂CH₂CO₂CH₂CH₃ 110. H OCH₂C₆H₅ CH₂CH₂CO₂H 111. H OCH₂CH₂C₆H₅ CH₂CO₂CH₂CH₂CH₃ 112. H OCH₂CH₂C₆H₅ CH₂CH₂CO₂H 113. H OCH₂CONH₂ CH₂CH₂CO₂CH₂CH₃ 114. H OCH₂CONH₂ CH₂CH₂CO₂H 115. H H CH₂CH₂PO(OCH₂CH₃)₂ 116. H H CH₂CH₂PO(OH)₂ 117. OH H CH₂CH₂PO(OCH₂CH₃)₂ 118. OH H CH₂CH₂PO(OH)₂ 119. OCH₃ H CH₂CH₂PO(OCH₂CH₃)₂ 120. OCH₃ H CH₂CH₂PO(OH)₂ 121. OCH₂CH═CH₂ H CH₂CH₂PO(OCH₂CH₃)₂ 122. OCH₂CH═CH₂ H CH₂CH₂PO(OH)₂ 123. OCH₂C₆H₅ H CH₂CH₂PO(OCH₂CH₃)₂ 124. OCH₂C₆H₅ H CH₂CH₂PO(OH)₂ 125. OCH₂CH₂C₆H₅ H CH₂CH₂PO(OCH₂CH₃)₂ 126. OCH₂CH₂C₆H₅ H CH₂CH₂PO(OH)₂ 127. OCH₂CONH₂ H CH₂CH₂PO(OCH₂CH₃)₂ 128. OCH₂CONH₂ H CH₂CH₂PO(OH)₂ 129. H Cl CH₂CH₂PO(OCH₂CH₃)₂ 130. H Cl CH₂CH₂PO(OH)₂ 131. Br H CH₂CH₂PO(OCH₂CH₃)₂ 132. Br H CH₂CH₂PO(OH)₂ 133. H CH₃ CH₂CH₂PO(OCH₂CH₃)₂ 134. H CH₃ CH₂CH₂PO(OH)₂ 135. NO₂ H CH₂CH₂PO(OCH₂CH₃)₂ 136. NO₂ H CH₂CH₂PO(OH)₂ 137. NH₂ H CH₂CH₂PO(OCH₂CH₃)₂ 138. NH₂ H CH₂CH₂PO(OH)₂ 139. NHSO₂CH₃ H CH₂CH₂PO(OCH₂CH₃)₂ 140. NHSO₂CH₃ H CH₂CH₂PO(OH)₂ 141. H OH CH₂CH₂PO(OCH₂CH₃)₂ 142. H OH CH₂CH₂PO(OH)₂ 143. H OCH₃ CH₂CH₂PO(OCH₂CH₃)₂ 144. H OCH₃ CH₂CH₂PO(OH)₂ 145. H OCH₂CH═CH₂ CH₂CH₂PO(OCH₂CH₃)₂ 146. H OCH₂CH═CH₂ CH₂CH₂PO(OH)₂ 147. H OCH₂C₆H₅ CH₂CH₂PO(OCH₂CH₃)₂ 148. H OCH₂C₆H₅ CH₂CH₂PO(OH)₂ 149. H OCH₂CH₂C₆H₅ CH₂CH₂PO(OCH₂CH₃)₂ 150. H OCH₂CH₂C₆H₅ CH₂CH₂PO(OH)₂ 151. H OCH₂CONH₂ CH₂CH₂PO(OCH₂CH₃)₂ 152. H OCH₂CONH₂ CH₂CH₂PO(OH)₂ 153. H H CH₂CH═CHCO₂CH₂CH₃ 154. H H CH₂CH═CHCO₂H 155. OH H CH₂CH═CHCO₂CH₂CH₃ 156. OH H CH₂CH═CHCO₂H 157. OCH₃ H CH₂CH═CHCO₂CH₂CH₃ 158. OCH₃ H CH₂CH═CHCO₂H 159. OCH₂CH═CH₂ H CH₂CH═CHCO₂CH₂CH₃ 160. OCH₂CH═CH₂ H CH₂CH═CHCO₂H 161. OCH₂C₆H₅ H CH₂CH═CHCO₂CH₂CH₃ 162. OCH₂C₆H₅ H CH₂CH═CHCO₂H 163. OCH₂CH₂C₆H₅ H CH₂CH═CHCO₂CH₂CH₃ 164. OCH₂CH₂C₆H₅ H CH₂CH═CHCO₂H 165. OCH₂CONH₂ H CH₂CH═CHCO₂CH₂CH₃ 166. OCH₂CONH₂ H CH₂CH═CHCO₂H 167. H Cl CH₂CH═CHCO₂CH₂CH₃ 168. H Cl CH₂CH═CHCO₂H 169. Br H CH₂CH═CHCO₂CH₂CH₃ 170. Br H CH₂CH═CHCO₂H 171. H CH₃ CH₂CH═CHCO₂CH₂CH₃ 172. H CH₃ CH₂CH═CHCO₂H 173. NO₂ H CH₂CH═CHCO₂CH₂CH₃ 174. NO₂ H CH₂CH═CHCO₂H 175. NH₂ H CH₂CH═CHCO₂CH₂CH₃ 176. NH₂ H CH₂CH═CHCO₂H 177. NHSO₂CH₃ H CH₂CH═CHCO₂CH₂CH₃ 178. NHSO₂CH₃ H CH₂CH═CHCO₂H 179. H OH CH₂CH═CHCO₂CH₂CH₃ 180. H OH CH₂CH═CHCO₂H 181. H OCH₃ CH₂CH═CHCO₂CH₂CH₃ 182. H OCH₃ CH₂CH═CHCO₂H 183. H OCH₂CH═CH₂ CH₂CH═CHCO₂CH₂CH₃ 184. H OCH₂CH═CH₂ CH₂CH═CHCO₂H 185. H OCH₂C₆H₅ CH₂CH═CHCO₂CH₂CH₃ 186. H OCH₂C₆H₅ CH₂CH═CHCO₂H 187. H OCH₂CH₂C₆H₅ CH₂CH═CHCO₂CH₂CH₃ 188. H OCH₂CH₂C₆H₅ CH₂CH═CHCO₂H 189. H OCH₂CONH₂ CH₂CH═CHCO₂CH₂CH₃ 190. H OCH₂CONH₂ CH₂CH═CHCO₂H

TABLE III

Ex. # X X¹ R¹ R″ 1. H H H CH₂—CO₂CH₂CH₃ 2. H H CH₃ CH₂—CO₂H 3. OH H H CH₂—CO₂CH₂CH₃ 4. OH H CH₃ CH₂—CO₂H 5. OCH₃ H H CH₂—CO₂CH₂CH₃ 6. OCH₃ H CH₃ CH₂—CO₂H 7. OCH₂CH═CH₂ H H CH₂—CO₂CH₂CH₃ 8. OCH₂CH═CH₂ H CH₃ CH₂—CO₂H 9. OCH₂C₆H₅ H H CH₂—CO₂CH₂CH₃ 10. OCH₂C₆H₅ H CH₃ CH₂—CO₂H 11. OCH₂CH₂C₆H₅ H H CH₂—CO₂CH₂CH₃ 12. OCH₂CH₂C₆H₅ H CH₃ CH₂—CO₂H 13. OCH₂—CONH₂ H H CH₂—CO₂CH₂CH₃ 14. OCH₂—CONH₂ H CH₃ CH₂—CO₂H 15. H Cl H CH₂—CO₂CH₂CH₃ 16. H Cl CH₃ CH₂—CO₂H 17. Br H H CH₂—CO₂CH₂CH₃ 18. Br H CH₃ CH₂—CO₂H 19. H CH₃ H CH₂—CO₂CH₂CH₃ 20. H CH₃ CH₃ CH₂—CO₂H 21. NO₂ H H CH₂—CO₂CH₂CH₃ 22. NO₂ H CH₃ CH₂—CO₂H 23. NH₂ H H CH₂—CO₂CH₂CH₃ 24. NH₂ H CH₃ CH₂—CO₂H 25. NHSO₂CH₃ H H CH₂—CO₂CH₂CH₃ 26. NHSO₂CH₃ H CH₃ CH₂—CO₂H 27. H OH H CH₂—CO₂CH₂CH₃ 28. H OH CH₃ CH₂—CO₂H 29. H OCH₃ H CH₂—CO₂CH₂CH₃ 30. H OCH₃ CH₃ CH₂—CO₂H 31. H OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ 32. H OCH₂CH═CH₂ CH₃ CH₂—CO₂H 33. H OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ 34. H OCH₂C₆H₅ CH₃ CH₂—CO₂H 35. H OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ 36. H OCH₂CH₂C₆H₅ CH₃ CH₂—CO₂H 37. H OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ 38. H OCH₂—CONH₂ CH₃ CH₂—CO₂H 39. H H H CH₂CH₂—CO₂CH₂CH₃ 40. H H CH₃ CH₂CH₂—CO₂H 41. OH H H CH₂CH₂—CO₂CH₂CH₃ 42. OH H CH₃ CH₂CH₂—CO₂H 43. OCH₃ H H CH₂CH₂—CO₂CH₂CH₃ 44. OCH₃ H CH₃ CH₂CH₂—CO₂H 45. OCH₂CH═CH₂ H H CH₂CH₂—CO₂CH₂CH₃ 46. OCH₂CH═CH₂ H CH₃ CH₂CH₂—CO₂H 47. OCH₂C₆H₅ H H CH₂CH₂—CO₂CH₂CH₃ 48. OCH₂C₆H₅ H CH₃ CH₂CH₂—CO₂H 49. OCH₂CH₂C₆H₅ H H CH₂CH₂—CO₂CH₂CH₃ 50. OCH₂CH₂C₆H₅ H CH₃ CH₂CH₂—CO₂H 51. OCH₂—CONH₂ H H CH₂CH₂—CO₂CH₂CH₃ 52. OCH₂—CONH₂ H CH₃ CH₂CH₂—CO₂H 53. H Cl H CH₂CH₂—CO₂CH₂CH₃ 54. H Cl CH₃ CH₂CH₂—CO₂H 55. Br H H CH₂CH₂—CO₂CH₂CH₃ 56. Br H CH₃ CH₂CH₂—CO₂H 57. H CH₃ H CH₂CH₂—CO₂CH₂CH₃ 58. H CH₃ CH₃ CH₂CH₂—CO₂H 59. NO₂ H H CH₂CH₂—CO₂CH₂CH₃ 60. NO₂ H CH₃ CH₂CH₂—CO₂H 61. NH₂ H H CH₂CH₂—CO₂CH₂CH₃ 62. NH₂ H CH₃ CH₂CH₂—CO₂H 63. NHSO₂CH₃ H H CH₂CH₂—CO₂CH₂CH₃ 64. NHSO₂CH₃ H CH₃ CH₂CH₂—CO₂H 65. H OH H CH₂CH₂—CO₂CH₂CH₃ 66. H OH CH₃ CH₂CH₂—CO₂H 67. H OCH₃ H CH₂CH₂—CO₂CH₂CH₃ 68. H OCH₃ CH₃ CH₂CH₂—CO₂H 69. H OCH₂CH═CH₂ H CH₂CH₂—CO₂CH₂CH₃ 70. H OCH₂CH═CH₂ CH₃ CH₂CH₂—CO₂H 71. H OCH₂C₆H₅ H CH₂CH₂—CO₂CH₂CH₃ 72. H OCH₂C₆H₅ CH₃ CH₂CH₂—CO₂H 73. H OCH₂CH₂C₆H₅ H CH₂CH₂—CO₂CH₂CH₃ 74. H OCH₂CH₂C₆H₅ CH₃ CH₂CH₂—CO₂H 75. H OCH₂—CONH₂ H CH₂CH₂—CO₂CH₂CH₃ 76. H OCH₂—CONH₂ CH₃ CH₂CH₂—CO₂H 77. H H H CH₂CH₂P—O(OCH₂CH₃)₂ 78. H H CH₃ CH₂CH₂P—O(OH)₂ 79. OH H H CH₂CH₂P—O(OCH₂CH₃)₂ 80. OH H CH₃ CH₂CH₂P—O(OH)₂ 81. OCH₃ H H CH₂CH₂P—O(OCH₂CH₃)₂ 82. OCH₃ H CH₃ CH₂CH₂P—O(OH)₂ 83. OCH₂CH═CH₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 84. OCH₂CH═CH₂ H CH₃ CH₂CH₂P—O(OH)₂ 85. OCH₂C₆H₅ H H CH₂CH₂P—O(OCH₂CH₃)₂ 86. OCH₂C₆H₅ H CH₃ CH₂CH₂P—O(OH)₂ 87. OCH₂CH₂C₆H₅ H H CH₂CH₂P—O(OCH₂CH₃)₂ 88. OCH₂CH₂C₆H₅ H CH₃ CH₂CH₂P—O(OH)₂ 89. OCH₂—CONH₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 90. OCH₂—CONH₂ H CH₃ CH₂CH₂P—O(OH)₂ 91. H Cl H CH₂CH₂P—O(OCH₂CH₃)₂ 92. H Cl CH₃ CH₂CH₂P—O(OH)₂ 93. Br H H CH₂CH₂P—O(OCH₂CH₃)₂ 94. Br H CH₃ CH₂CH₂P—O(OH)₂ 95. H CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ 96. H CH₃ CH₃ CH₂CH₂P—O(OH)₂ 97. NO₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 98. NO₂ H CH₃ CH₂CH₂P—O(OH)₂ 99. NH₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 100. NH₂ H CH₃ CH₂CH₂P—O(OH)₂ 101. NHSO₂CH₃ H H CH₂CH₂P—O(OCH₂CH₃)₂ 102. NHSO₂CH₃ H CH₃ CH₂CH₂P—O(OH)₂ 103. H OH H CH₂CH₂P—O(OCH₂CH₃)₂ 104. H OH CH₃ CH₂CH₂P—O(OH)₂ 105. H OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ 106. H OCH₃ CH₃ CH₂CH₂P—O(OH)₂ 107. H OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ 108. H OCH₂CH═CH₂ CH₃ CH₂CH₂P—O(OH)₂ 109. H OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ 110. H OCH₂C₆H₅ CH₃ CH₂CH₂P—O(OH)₂ 111. H OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ 112. H OCH₂CH₂C₆H₅ CH₃ CH₂CH₂P—O(OH)₂ 113. H OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ 114. H OCH₂—CONH₂ CH₃ CH₂CH₂P—O(OH)₂ 115. H H H CH₂CH═CH—CO₂CH₂CH₃ 116. H H CH₃ CH₂CH═CH—CO₂H 117. OH H H CH₂CH═CH—CO₂CH₂CH₃ 118. OH H CH₃ CH₂CH═CH—CO₂H 119. OCH₃ H H CH₂CH═CH—CO₂CH₂CH₃ 120. OCH₃ H CH₃ CH₂CH═CH—CO₂H 121. OCH₂CH═CH₂ H H CH₂CH═CH—CO₂CH₂CH₃ 122. OCH₂CH═CH₂ H CH₃ CH₂CH═CH—CO₂H 123. OCH₂C₆H₅ H H CH₂CH═CH—CO₂CH₂CH₃ 124. OCH₂C₆H₅ H CH₃ CH₂CH═CH—CO₂H 125. OCH₂CH₂C₆H₅ H H CH₂CH═CH—CO₂CH₂CH₃ 126. OCH₂CH₂C₆H₅ H CH₃ CH₂CH═CH—CO₂H 127. OCH₂—CONH₂ H H CH₂CH═CH—CO₂CH₂CH₃ 128. OCH₂—CONH₂ H CH₃ CH₂CH═CH—CO₂H 129. H Cl H CH₂CH═CH—CO₂CH₂CH₃ 130. H Cl CH₃ CH₂CH═CH—CO₂H 131. Br H H CH₂CH═CH—CO₂CH₂CH₃ 132. Br H CH₃ CH₂CH═CH—CO₂H 133. H CH₃ H CH₂CH═CH—CO₂CH₂CH₃ 134. H CH₃ CH₃ CH₂CH═CH—CO₂H 135. NO₂ H H CH₂CH═CH—CO₂CH₂CH₃ 136. NO₂ H CH₃ CH₂CH═CH—CO₂H 137. NH₂ H H CH₂CH═CH—CO₂CH₂CH₃ 138. NH₂ H CH₃ CH₂CH═CH—CO₂H 139. NHSO₂CH₃ H H CH₂CH═CH—CO₂CH₂CH₃ 140. NHSO₂CH₃ H CH₃ CH₂CH═CH—CO₂H 141. H OH H CH₂CH═CH—CO₂CH₂CH₃ 142. H OH CH₃ CH₂CH═CH—CO₂H 143. H OCH₃ H CH₂CH═CH—CO₂CH₂CH₃ 144. H OCH₃ CH₃ CH₂CH═CH—CO₂H 145. H OCH₂CH═CH₂ H CH₂CH═CH—CO₂CH₂CH₃ 146. H OCH₂CH═CH₂ CH₃ CH₂CH═CH—CO₂H 147. H OCH₂C₆H₅ H CH₂CH═CH—CO₂CH₂CH₃ 148. H OCH₂C₆H₅ CH₃ CH₂CH═CH—CO₂H 149. H OCH₂CH₂C₆H₅ H CH₂CH═CH—CO₂CH₂CH₃ 150. H OCH₂CH₂C₆H₅ CH₃ CH₂CH═CH—CO₂H 151. H OCH₂—CONH₂ H CH₂CH═CH—CO₂CH₂CH₃ 152. H OCH₂—CONH₂ CH₃ CH₂CH═CH—CO₂H 153. H H CH₂—CO₂CH₂CH₃ CH₃ 154. H H CH₂—CO₂H CH₃ 155. OH H CH₂—CO₂CH₂CH₃ CH₃ 156. OH H CH₂—CO₂H CH₃ 157. OCH₃ H CH₂—CO₂CH₂CH₃ CH₃ 158. OCH₃ H CH₂—CO₂H CH₃ 159. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₃ 160. OCH₂CH═CH₂ H CH₂—CO₂H CH₃ 161. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₃ 162. OCH₂C₆H₅ H CH₂—CO₂H CH₃ 163. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₃ 164. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₃ 165. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₃ 166. OCH₂—CONH₂ H CH₂—CO₂H CH₃ 167. H Cl CH₂—CO₂CH₂CH₃ CH₃ 168. H Cl CH₂—CO₂H CH₃ 169. Br H CH₂—CO₂CH₂CH₃ CH₃ 170. Br H CH₂—CO₂H CH₃ 171. H CH₃ CH₂—CO₂CH₂CH₃ CH₃ 172. H CH₃ CH₂—CO₂H CH₃ 173. NO₂ H CH₂—CO₂CH₂CH₃ CH₃ 174. NO₂ H CH₂—CO₂H CH₃ 175. NH₂ H CH₂—CO₂CH₂CH₃ CH₃ 176. NH₂ H CH₂—CO₂H CH₃ 177. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₃ 178. NHSO₂CH₃ H CH₂—CO₂H CH₃ 179. H OH CH₂—CO₂CH₂CH₃ CH₃ 180. H OH CH₂—CO₂H CH₃ 181. H OCH₃ CH₂—CO₂CH₂CH₃ CH₃ 182. H OCH₃ CH₂—CO₂H CH₃ 183. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₃ 184. H OCH₂CH═CH₂ CH₂—CO₂H CH₃ 185. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₃ 186. H OCH₂C₆H₅ CH₂—CO₂H CH₃ 187. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₃ 188. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₃ 189. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₃ 190. H OCH₂—CONH₂ CH₂—CO₂H CH₃ 191. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 192. H H CH₂CH₂P—O(OH)₂ CH₃ 193. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 194. OH H CH₂CH₂P—O(OH)₂ CH₃ 195. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 196. OCH₃ H CH₂CH₂P—O(OH)₂ CH₃ 197. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 198. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₃ 199. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 200. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₃ 201. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 202. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₃ 203. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 204. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₃ 205. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 206. H Cl CH₂CH₂P—O(OH)₂ CH₃ 207. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 208. Br H CH₂CH₂P—O(OH)₂ CH₃ 209. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 210. H CH₃ CH₂CH₂P—O(OH)₂ CH₃ 211. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 212. NO₂ H CH₂CH₂P—O(OH)₂ CH₃ 213. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 214. NH₂ H CH₂CH₂P—O(OH)₂ CH₃ 215. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 216. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₃ 217. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 218. H OH CH₂CH₂P—O(OH)₂ CH₃ 219. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 220. H OCH₃ CH₂CH₂P—O(OH)₂ CH₃ 221. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 222. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₃ 223. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 224. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₃ 225. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 226. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₃ 227. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 228. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₃ 229. H H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 230. H H CH₂—CO₂H CH₂CH═CH₂ 231. OH H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 232. OH H CH₂—CO₂H CH₂CH═CH₂ 233. OCH₃ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 234. OCH₃ H CH₂—CO₂H CH₂CH═CH₂ 235. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 236. OCH₂CH═CH₂ H CH₂—CO₂H CH₂CH═CH₂ 237. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 238. OCH₂C₆H₅ H CH₂—CO₂H CH₂CH═CH₂ 239. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 240. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₂CH═CH₂ 241. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 242. OCH₂—CONH₂ H CH₂—CO₂H CH₂CH═CH₂ 243. H Cl CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 244. H Cl CH₂—CO₂H CH₂CH═CH₂ 245. Br H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 246. Br H CH₂—CO₂H CH₂CH═CH₂ 247. H CH₃ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 248. H CH₃ CH₂—CO₂H CH₂CH═CH₂ 249. NO₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 250. NO₂ H CH₂—CO₂H CH₂CH═CH₂ 251. NH₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 252. NH₂ H CH₂—CO₂H CH₂CH═CH₂ 253. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 254. NHSO₂CH₃ H CH₂—CO₂H CH₂CH═CH₂ 255. H OH CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 256. H OH CH₂—CO₂H CH₂CH═CH₂ 257. H OCH₃ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 258. H OCH₃ CH₂—CO₂H CH₂CH═CH₂ 259. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 260. H OCH₂CH═CH₂ CH₂—CO₂H CH₂CH═CH₂ 261. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 262. H OCH₂C₆H₅ CH₂—CO₂H CH₂CH═CH₂ 263. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 264. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₂CH═CH₂ 265. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 266. H OCH₂—CONH₂ CH₂—CO₂H CH₂CH═CH₂ 267. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 268. H H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 269. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 270. OH H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 271. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 272. OCH₃ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 273. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 274. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 275. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 276. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 277. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 278. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 279. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 280. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 281. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 282. H Cl CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 283. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 284. Br H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 285. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 286. H CH₃ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 287. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 288. NO₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 289. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 290. NH₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 291. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 292. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 293. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 294. H OH CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 295. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 296. H OCH₃ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 297. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 298. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 299. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 300. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 301. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 302. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 303. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 304. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 305. H H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 306. H H CH₂—CO₂H CH₂—CONH₂ 307. OH H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 308. OH H CH₂—CO₂H CH₂—CONH₂ 309. OCH₃ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 310. OCH₃ H CH₂—CO₂H CH₂—CONH₂ 311. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 312. OCH₂CH═CH₂ H CH₂—CO₂H CH₂—CONH₂ 313. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 314. OCH₂C₆H₅ H CH₂—CO₂H CH₂—CONH₂ 315. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 316. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₂—CONH₂ 317. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 318. OCH₂—CONH₂ H CH₂—CO₂H CH₂—CONH₂ 319. H Cl CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 320. H Cl CH₂—CO₂H CH₂—CONH₂ 321. Br H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 322. Br H CH₂—CO₂H CH₂—CONH₂ 323. H CH₃ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 324. H CH₃ CH₂—CO₂H CH₂—CONH₂ 325. NO₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 326. NO₂ H CH₂—CO₂H CH₂—CONH₂ 327. NH₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 328. NH₂ H CH₂—CO₂H CH₂—CONH₂ 329. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 330. NHSO₂CH₃ H CH₂—CO₂H CH₂—CONH₂ 331. H OH CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 332. H OH CH₂—CO₂H CH₂—CONH₂ 333. H OCH₃ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 334. H OCH₃ CH₂—CO₂H CH₂—CONH₂ 335. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 336. H OCH₂CH═CH₂ CH₂—CO₂H CH₂—CONH₂ 337. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 338. H OCH₂C₆H₅ CH₂—CO₂H CH₂—CONH₂ 339. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 340. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₂—CONH₂ 341. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 342. H OCH₂—CONH₂ CH₂—CO₂H CH₂—CONH₂ 343. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 344. H H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 345. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 346. OH H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 347. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 348. OCH₃ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 349. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 350. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 351. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 352. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 353. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 354. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 355. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 356. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 357. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 358. H Cl CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 359. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 360. Br H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 361. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 362. H CH₃ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 363. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 364. NO₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 365. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 366. NH₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 367. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 368. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 369. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 370. H OH CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 371. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 372. H OCH₃ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 373. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 374. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 375. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 376. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 377. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 378. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 379. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 380. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 381. H H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 382. H H CH₂—CO₂H CH₂C₆H₅ 383. OH H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 384. OH H CH₂—CO₂H CH₂C₆H₅ 385. OCH₃ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 386. OCH₃ H CH₂—CO₂H CH₂C₆H₅ 387. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 388. OCH₂CH═CH₂ H CH₂—CO₂H CH₂C₆H₅ 389. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 390. OCH₂C₆H₅ H CH₂—CO₂H CH₂C₆H₅ 391. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 392. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₂C₆H₅ 393. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 394. OCH₂—CONH₂ H CH₂—CO₂H CH₂C₆H₅ 395. H Cl CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 396. H Cl CH₂—CO₂H CH₂C₆H₅ 397. Br H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 398. Br H CH₂—CO₂H CH₂C₆H₅ 399. H CH₃ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 400. H CH₃ CH₂—CO₂H CH₂C₆H₅ 401. NO₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 402. NO₂ H CH₂—CO₂H CH₂C₆H₅ 403. NH₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 404. NH₂ H CH₂—CO₂H CH₂C₆H₅ 405. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 406. NHSO₂CH₃ H CH₂—CO₂H CH₂C₆H₅ 407. H OH CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 408. H OH CH₂—CO₂H CH₂C₆H₅ 409. H OCH₃ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 410. H OCH₃ CH₂—CO₂H CH₂C₆H₅ 411. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 412. H OCH₂CH═CH₂ CH₂—CO₂H CH₂C₆H₅ 413. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 414. H OCH₂C₆H₅ CH₂—CO₂H CH₂C₆H₅ 415. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 416. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₂C₆H₅ 417. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 418. H OCH₂—CONH₂ CH₂—CO₂H CH₂C₆H₅ 419. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 420. H H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 421. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 422. OH H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 423. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 424. OCH₃ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 425. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 426. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 427. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 428. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 429. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 430. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 431. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 432. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 433. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 434. H Cl CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 435. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 436. Br H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 437. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 438. H CH₃ CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 439. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 440. NO₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 441. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 442. NH₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 443. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 444. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 445. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 446. H OH CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 447. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 448. H OCH₃ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 449. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 450. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 451. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 452. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 453. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 454. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 455. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 456. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂

TABLE IV

Ex. # X X¹ R¹ R″ 1. H H H CH₂—CO₂CH₂CH₃ 2. H H CH₃ CH₂—CO₂H 3. OH H H CH₂—CO₂CH₂CH₃ 4. OH H CH₃ CH₂—CO₂H 5. OCH₃ H H CH₂—CO₂CH₂CH₃ 6. OCH₃ H CH₃ CH₂—CO₂H 7. OCH₂CH═CH₂ H H CH₂—CO₂CH₂CH₃ 8. OCH₂CH═CH₂ H CH₃ CH₂—CO₂H 9. OCH₂C₆H₅ H H CH₂—CO₂CH₂CH₃ 10. OCH₂C₆H₅ H CH₃ CH₂—CO₂H 11. OCH₂CH₂C₆H₅ H H CH₂—CO₂CH₂CH₃ 12. OCH₂CH₂C₆H₅ H CH₃ CH₂—CO₂H 13. OCH₂—CONH₂ H H CH₂—CO₂CH₂CH₃ 14. OCH₂—CONH₂ H CH₃ CH₂—CO₂H 15. H Cl H CH₂—CO₂CH₂CH₃ 16. H Cl CH₃ CH₂—CO₂H 17. Br H H CH₂—CO₂CH₂CH₃ 18. Br H CH₃ CH₂—CO₂H 19. H CH₃ H CH₂—CO₂CH₂CH₃ 20. H CH₃ CH₃ CH₂—CO₂H 21. NO₂ H H CH₂—CO₂CH₂CH₃ 22. NO₂ H CH₃ CH₂—CO₂H 23. NH₂ H H CH₂—CO₂CH₂CH₃ 24. NH₂ H CH₃ CH₂—CO₂H 25. NHSO₂CH₃ H H CH₂—CO₂CH₂CH₃ 26. NHSO₂CH₃ H CH₃ CH₂—CO₂H 27. H OH H CH₂—CO₂CH₂CH₃ 28. H OH CH₃ CH₂—CO₂H 29. H OCH₃ H CH₂—CO₂CH₂CH₃ 30. H OCH₃ CH₃ CH₂—CO₂H 31. H OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ 32. H OCH₂CH═CH₂ CH₃ CH₂—CO₂H 33. H OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ 34. H OCH₂C₆H₅ CH₃ CH₂—CO₂H 35. H OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ 36. H OCH₂CH₂C₆H₅ CH₃ CH₂—CO₂H 37. H OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ 38. H OCH₂—CONH₂ CH₃ CH₂—CO₂H 39. H H H CH₂CH₂—CO₂CH₂CH₃ 40. H H CH₃ CH₂CH₂—CO₂H 41. OH H H CH₂CH₂—CO₂CH₂CH₃ 42. OH H CH₃ CH₂CH₂—CO₂H 43. OCH₃ H H CH₂CH₂—CO₂CH₂CH₃ 44. OCH₃ H CH₃ CH₂CH₂—CO₂H 45. OCH₂CH═CH₂ H H CH₂CH₂—CO₂CH₂CH₃ 46. OCH₂CH═CH₂ H CH₃ CH₂CH₂—CO₂H 47. OCH₂C₆H₅ H H CH₂CH₂—CO₂CH₂CH₃ 48. OCH₂C₆H₅ H CH₃ CH₂CH₂—CO₂H 49. OCH₂CH₂C₆H₅ H H CH₂CH₂—CO₂CH₂CH₃ 50. OCH₂CH₂C₆H₅ H CH₃ CH₂CH₂—CO₂H 51. OCH₂—CONH₂ H H CH₂CH₂—CO₂CH₂CH₃ 52. OCH₂—CONH₂ H CH₃ CH₂CH₂—CO₂H 53. H Cl H CH₂CH₂—CO₂CH₂CH₃ 54. H Cl CH₃ CH₂CH₂—CO₂H 55. Br H H CH₂CH₂—CO₂CH₂CH₃ 56. Br H CH₃ CH₂CH₂—CO₂H 57. H CH₃ H CH₂CH₂—CO₂CH₂CH₃ 58. H CH₃ CH₃ CH₂CH₂—CO₂H 59. NO₂ H H CH₂CH₂—CO₂CH₂CH₃ 60. NO₂ H CH₃ CH₂CH₂—CO₂H 61. NH₂ H H CH₂CH₂—CO₂CH₂CH₃ 62. NH₂ H CH₃ CH₂CH₂—CO₂H 63. NHSO₂CH₃ H H CH₂CH₂—CO₂CH₂CH₃ 64. NHSO₂CH₃ H CH₃ CH₂CH₂—CO₂H 65. H OH H CH₂CH₂—CO₂CH₂CH₃ 66. H OH CH₃ CH₂CH₂—CO₂H 67. H OCH₃ H CH₂CH₂—CO₂CH₂CH₃ 68. H OCH₃ CH₃ CH₂CH₂—CO₂H 69. H OCH₂CH═CH₂ H CH₂CH₂—CO₂CH₂CH₃ 70. H OCH₂CH═CH₂ CH₃ CH₂CH₂—CO₂H 71. H OCH₂C₆H₅ H CH₂CH₂—CO₂CH₂CH₃ 72. H OCH₂C₆H₅ CH₃ CH₂CH₂—CO₂H 73. H OCH₂CH₂C₆H₅ H CH₂CH₂—CO₂CH₂CH₃ 74. H OCH₂CH₂C₆H₅ CH₃ CH₂CH₂—CO₂H 75. H OCH₂—CONH₂ H CH₂CH₂—CO₂CH₂CH₃ 76. H OCH₂—CONH₂ CH₃ CH₂CH₂—CO₂H 77. H H H CH₂CH₂P—O(OCH₂CH₃)₂ 78. H H CH₃ CH₂CH₂P—O(OH)₂ 79. OH H H CH₂CH₂P—O(OCH₂CH₃)₂ 80. OH H CH₃ CH₂CH₂P—O(OH)₂ 81. OCH₃ H H CH₂CH₂P—O(OCH₂CH₃)₂ 82. OCH₃ H CH₃ CH₂CH₂P—O(OH)₂ 83. OCH₂CH═CH₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 84. OCH₂CH═CH₂ H CH₃ CH₂CH₂P—O(OH)₂ 85. OCH₂C₆H₅ H H CH₂CH₂P—O(OCH₂CH₃)₂ 86. OCH₂C₆H₅ H CH₃ CH₂CH₂P—O(OH)₂ 87. OCH₂CH₂C₆H₅ H H CH₂CH₂P—O(OCH₂CH₃)₂ 88. OCH₂CH₂C₆H₅ H CH₃ CH₂CH₂P—O(OH)₂ 89. OCH₂—CONH₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 90. OCH₂—CONH₂ H CH₃ CH₂CH₂P—O(OH)₂ 91. H Cl H CH₂CH₂P—O(OCH₂CH₃)₂ 92. H Cl CH₃ CH₂CH₂P—O(OH)₂ 93. Br H H CH₂CH₂P—O(OCH₂CH₃)₂ 94. Br H CH₃ CH₂CH₂P—O(OH)₂ 95. H CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ 96. H CH₃ CH₃ CH₂CH₂P—O(OH)₂ 97. NO₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 98. NO₂ H CH₃ CH₂CH₂P—O(OH)₂ 99. NH₂ H H CH₂CH₂P—O(OCH₂CH₃)₂ 100. NH₂ H CH₃ CH₂CH₂P—O(OH)₂ 101. NHSO₂CH₃ H H CH₂CH₂P—O(OCH₂CH₃)₂ 102. NHSO₂CH₃ H CH₃ CH₂CH₂P—O(OH)₂ 103. H OH H CH₂CH₂P—O(OCH₂CH₃)₂ 104. H OH CH₃ CH₂CH₂P—O(OH)₂ 105. H OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ 106. H OCH₃ CH₃ CH₂CH₂P—O(OH)₂ 107. H OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ 108. H OCH₂CH═CH₂ CH₃ CH₂CH₂P—O(OH)₂ 109. H OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ 110. H OCH₂C₆H₅ CH₃ CH₂CH₂P—O(OH)₂ 111. H OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ 112. H OCH₂CH₂C₆H₅ CH₃ CH₂CH₂P—O(OH)₂ 113. H OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ 114. H OCH₂—CONH₂ CH₃ CH₂CH₂P—O(OH)₂ 115. H H H CH₂CH═CH—CO₂CH₂CH₃ 116. H H CH₃ CH₂CH═CH—CO₂H 117. OH H H CH₂CH═CH—CO₂CH₂CH₃ 118. OH H CH₃ CH₂CH═CH—CO₂H 119. OCH₃ H H CH₂CH═CH—CO₂CH₂CH₃ 120. OCH₃ H CH₃ CH₂CH═CH—CO₂H 121. OCH₂CH═CH₂ H H CH₂CH═CH—CO₂CH₂CH₃ 122. OCH₂CH═CH₂ H CH₃ CH₂CH═CH—CO₂H 123. OCH₂C₆H₅ H H CH₂CH═CH—CO₂CH₂CH₃ 124. OCH₂C₆H₅ H CH₃ CH₂CH═CH—CO₂H 125. OCH₂CH₂C₆H₅ H H CH₂CH═CH—CO₂CH₂CH₃ 126. OCH₂CH₂C₆H₅ H CH₃ CH₂CH═CH—CO₂H 127. OCH₂—CONH₂ H H CH₂CH═CH—CO₂CH₂CH₃ 128. OCH₂—CONH₂ H CH₃ CH₂CH═CH—CO₂H 129. H Cl H CH₂CH═CH—CO₂CH₂CH₃ 130. H Cl CH₃ CH₂CH═CH—CO₂H 131. Br H H CH₂CH═CH—CO₂CH₂CH₃ 132. Br H CH₃ CH₂CH═CH—CO₂H 133. H CH₃ H CH₂CH═CH—CO₂CH₂CH₃ 134. H CH₃ CH₃ CH₂CH═CH—CO₂H 135. NO₂ H H CH₂CH═CH—CO₂CH₂CH₃ 136. NO₂ H CH₃ CH₂CH═CH—CO₂H 137. NH₂ H H CH₂CH═CH—CO₂CH₂CH₃ 138. NH₂ H CH₃ CH₂CH═CH—CO₂H 139. NHSO₂CH₃ H H CH₂CH═CH—CO₂CH₂CH₃ 140. NHSO₂CH₃ H CH₃ CH₂CH═CH—CO₂H 141. H OH H CH₂CH═CH—CO₂CH₂CH₃ 142. H OH CH₃ CH₂CH═CH—CO₂H 143. H OCH₃ H CH₂CH═CH—CO₂CH₂CH₃ 144. H OCH₃ CH₃ CH₂CH═CH—CO₂H 145. H OCH₂CH═CH₂ H CH₂CH═CH—CO₂CH₂CH₃ 146. H OCH₂CH═CH₂ CH₃ CH₂CH═CH—CO₂H 147. H OCH₂C₆H₅ H CH₂CH═CH—CO₂CH₂CH₃ 148. H OCH₂C₆H₅ CH₃ CH₂CH═CH—CO₂H 149. H OCH₂CH₂C₆H₅ H CH₂CH═CH—CO₂CH₂CH₃ 150. H OCH₂CH₂C₆H₅ CH₃ CH₂CH═CH—CO₂H 151. H OCH₂—CONH₂ H CH₂CH═CH—CO₂CH₂CH₃ 152. H OCH₂—CONH₂ CH₃ CH₂CH═CH—CO₂H 153. H H CH₂—CO₂CH₂CH₃ CH₃ 154. H H CH₂—CO₂H CH₃ 155. OH H CH₂—CO₂CH₂CH₃ CH₃ 156. OH H CH₂—CO₂H CH₃ 157. OCH₃ H CH₂—CO₂CH₂CH₃ CH₃ 158. OCH₃ H CH₂—CO₂H CH₃ 159. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₃ 160. OCH₂CH═CH₂ H CH₂—CO₂H CH₃ 161. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₃ 162. OCH₂C₆H₅ H CH₂—CO₂H CH₃ 163. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₃ 164. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₃ 165. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₃ 166. OCH₂—CONH₂ H CH₂—CO₂H CH₃ 167. H Cl CH₂—CO₂CH₂CH₃ CH₃ 168. H Cl CH₂—CO₂H CH₃ 169. Br H CH₂—CO₂CH₂CH₃ CH₃ 170. Br H CH₂—CO₂H CH₃ 171. H CH₃ CH₂—CO₂CH₂CH₃ CH₃ 172. H CH₃ CH₂—CO₂H CH₃ 173. NO₂ H CH₂—CO₂CH₂CH₃ CH₃ 174. NO₂ H CH₂—CO₂H CH₃ 175. NH₂ H CH₂—CO₂CH₂CH₃ CH₃ 176. NH₂ H CH₂—CO₂H CH₃ 177. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₃ 178. NHSO₂CH₃ H CH₂—CO₂H CH₃ 179. H OH CH₂—CO₂CH₂CH₃ CH₃ 180. H OH CH₂—CO₂H CH₃ 181. H OCH₃ CH₂—CO₂CH₂CH₃ CH₃ 182. H OCH₃ CH₂—CO₂H CH₃ 183. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₃ 184. H OCH₂CH═CH₂ CH₂—CO₂H CH₃ 185. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₃ 186. H OCH₂C₆H₅ CH₂—CO₂H CH₃ 187. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₃ 188. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₃ 189. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₃ 190. H OCH₂—CONH₂ CH₂—CO₂H CH₃ 191. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 192. H H CH₂CH₂P—O(OH)₂ CH₃ 193. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 194. OH H CH₂CH₂P—O(OH)₂ CH₃ 195. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 196. OCH₃ H CH₂CH₂P—O(OH)₂ CH₃ 197. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 198. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₃ 199. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 200. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₃ 201. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 202. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₃ 203. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 204. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₃ 205. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 206. H Cl CH₂CH₂P—O(OH)₂ CH₃ 207. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 208. Br H CH₂CH₂P—O(OH)₂ CH₃ 209. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 210. H CH₃ CH₂CH₂P—O(OH)₂ CH₃ 211. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 212. NO₂ H CH₂CH₂P—O(OH)₂ CH₃ 213. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 214. NH₂ H CH₂CH₂P—O(OH)₂ CH₃ 215. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 216. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₃ 217. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 218. H OH CH₂CH₂P—O(OH)₂ CH₃ 219. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 220. H OCH₃ CH₂CH₂P—O(OH)₂ CH₃ 221. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 222. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₃ 223. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 224. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₃ 225. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 226. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₃ 227. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₃ 228. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₃ 229. H H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 230. H H CH₂—CO₂H CH₂CH═CH₂ 231. OH H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 232. OH H CH₂—CO₂H CH₂CH═CH₂ 233. OCH₃ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 234. OCH₃ H CH₂—CO₂H CH₂CH═CH₂ 235. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 236. OCH₂CH═CH₂ H CH₂—CO₂H CH₂CH═CH₂ 237. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 238. OCH₂C₆H₅ H CH₂—CO₂H CH₂CH═CH₂ 239. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 240. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₂CH═CH₂ 241. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 242. OCH₂—CONH₂ H CH₂—CO₂H CH₂CH═CH₂ 243. H Cl CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 244. H Cl CH₂—CO₂H CH₂CH═CH₂ 245. Br H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 246. Br H CH₂—CO₂H CH₂CH═CH₂ 247. H CH₃ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 248. H CH₃ CH₂—CO₂H CH₂CH═CH₂ 249. NO₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 250. NO₂ H CH₂—CO₂H CH₂CH═CH₂ 251. NH₂ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 252. NH₂ H CH₂—CO₂H CH₂CH═CH₂ 253. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 254. NHSO₂CH₃ H CH₂—CO₂H CH₂CH═CH₂ 255. H OH CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 256. H OH CH₂—CO₂H CH₂CH═CH₂ 257. H OCH₃ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 258. H OCH₃ CH₂—CO₂H CH₂CH═CH₂ 259. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 260. H OCH₂CH═CH₂ CH₂—CO₂H CH₂CH═CH₂ 261. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 262. H OCH₂C₆H₅ CH₂—CO₂H CH₂CH═CH₂ 263. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 264. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₂CH═CH₂ 265. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₂CH═CH₂ 266. H OCH₂—CONH₂ CH₂—CO₂H CH₂CH═CH₂ 267. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 268. H H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 269. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 270. OH H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 271. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 272. OCH₃ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 273. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 274. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 275. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 276. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 277. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 278. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 279. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 280. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 281. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 282. H Cl CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 283. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 284. Br H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 285. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 286. H CH₃ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 287. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 288. NO₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 289. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 290. NH₂ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 291. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 292. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 293. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 294. H OH CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 295. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 296. H OCH₃ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 297. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 298. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 299. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 300. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 301. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 302. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 303. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂CH═CH₂ 304. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₂CH═CH₂ 305. H H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 306. H H CH₂—CO₂H CH₂—CONH₂ 307. OH H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 308. OH H CH₂—CO₂H CH₂—CONH₂ 309. OCH₃ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 310. OCH₃ H CH₂—CO₂H CH₂—CONH₂ 311. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 312. OCH₂CH═CH₂ H CH₂—CO₂H CH₂—CONH₂ 313. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 314. OCH₂C₆H₅ H CH₂—CO₂H CH₂—CONH₂ 315. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 316. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₂—CONH₂ 317. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 318. OCH₂—CONH₂ H CH₂—CO₂H CH₂—CONH₂ 319. H Cl CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 320. H Cl CH₂—CO₂H CH₂—CONH₂ 321. Br H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 322. Br H CH₂—CO₂H CH₂—CONH₂ 323. H CH₃ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 324. H CH₃ CH₂—CO₂H CH₂—CONH₂ 325. NO₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 326. NO₂ H CH₂—CO₂H CH₂—CONH₂ 327. NH₂ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 328. NH₂ H CH₂—CO₂H CH₂—CONH₂ 329. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 330. NHSO₂CH₃ H CH₂—CO₂H CH₂—CONH₂ 331. H OH CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 332. H OH CH₂—CO₂H CH₂—CONH₂ 333. H OCH₃ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 334. H OCH₃ CH₂—CO₂H CH₂—CONH₂ 335. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 336. H OCH₂CH═CH₂ CH₂—CO₂H CH₂—CONH₂ 337. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 338. H OCH₂C₆H₅ CH₂—CO₂H CH₂—CONH₂ 339. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 340. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₂—CONH₂ 341. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₂—CONH₂ 342. H OCH₂—CONH₂ CH₂—CO₂H CH₂—CONH₂ 343. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 344. H H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 345. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 346. OH H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 347. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 348. OCH₃ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 349. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 350. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 351. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 352. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 353. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 354. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 355. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 356. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 357. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 358. H Cl CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 359. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 360. Br H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 361. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 362. H CH₃ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 363. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 364. NO₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 365. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 366. NH₂ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 367. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 368. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 369. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 370. H OH CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 371. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 372. H OCH₃ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 373. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 374. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 375. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 376. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 377. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 378. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 379. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 380. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 381. H H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 382. H H CH₂—CO₂H CH₂C₆H₅ 383. OH H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 384. OH H CH₂—CO₂H CH₂C₆H₅ 385. OCH₃ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 386. OCH₃ H CH₂—CO₂H CH₂C₆H₅ 387. OCH₂CH═CH₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 388. OCH₂CH═CH₂ H CH₂—CO₂H CH₂C₆H₅ 389. OCH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 390. OCH₂C₆H₅ H CH₂—CO₂H CH₂C₆H₅ 391. OCH₂CH₂C₆H₅ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 392. OCH₂CH₂C₆H₅ H CH₂—CO₂H CH₂C₆H₅ 393. OCH₂—CONH₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 394. OCH₂—CONH₂ H CH₂—CO₂H CH₂C₆H₅ 395. H Cl CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 396. H Cl CH₂—CO₂H CH₂C₆H₅ 397. Br H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 398. Br H CH₂—CO₂H CH₂C₆H₅ 399. H CH₃ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 400. H CH₃ CH₂—CO₂H CH₂C₆H₅ 401. NO₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 402. NO₂ H CH₂—CO₂H CH₂C₆H₅ 403. NH₂ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 404. NH₂ H CH₂—CO₂H CH₂C₆H₅ 405. NHSO₂CH₃ H CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 406. NHSO₂CH₃ H CH₂—CO₂H CH₂C₆H₅ 407. H OH CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 408. H OH CH₂—CO₂H CH₂C₆H₅ 409. H OCH₃ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 410. H OCH₃ CH₂—CO₂H CH₂C₆H₅ 411. H OCH₂CH═CH₂ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 412. H OCH₂CH═CH₂ CH₂—CO₂H CH₂C₆H₅ 413. H OCH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 414. H OCH₂C₆H₅ CH₂—CO₂H CH₂C₆H₅ 415. H OCH₂CH₂C₆H₅ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 416. H OCH₂CH₂C₆H₅ CH₂—CO₂H CH₂C₆H₅ 417. H OCH₂—CONH₂ CH₂—CO₂CH₂CH₃ CH₂C₆H₅ 418. H OCH₂—CONH₂ CH₂—CO₂H CH₂C₆H₅ 419. H H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 420. H H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 421. OH H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 422. OH H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 423. OCH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 424. OCH₃ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 425. OCH₂CH═CH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 426. OCH₂CH═CH₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 427. OCH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 428. OCH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 429. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 430. OCH₂CH₂C₆H₅ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 431. OCH₂—CONH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 432. OCH₂—CONH₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 433. H Cl CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 434. H Cl CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 435. Br H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 436. Br H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 437. H CH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 438. H CH₃ CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 439. NO₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 440. NO₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 441. NH₂ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 442. NH₂ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 443. NHSO₂CH₃ H CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 444. NHSO₂CH₃ H CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 445. H OH CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 446. H OH CH₂CH₂P—O(OH)₂ CH₂C₆H₅ 447. H OCH₃ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂C₆H₅ 448. H OCH₃ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 449. H OCH₂CH═CH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 450. H OCH₂CH═CH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 451. H OCH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 452. H OCH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 453. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 454. H OCH₂CH₂C₆H₅ CH₂CH₂P—O(OH)₂ CH₂—CONH₂ 455. H OCH₂—CONH₂ CH₂CH₂P—O(OCH₂CH₃)₂ CH₂—CONH₂ 456. H OCH₂—CONH₂ CH₂CH₂P—O(OH)₂ CH₂—CONH₂

TABLE Va

Ex. # X X¹ X² X³ R¹ 1. OCH₂CO₂—CH₂CH₃ H H H H 2. OCH₂CO₂—CH₂CH₃ H H H CH₃ 3. OCH₂CO₂H H H H H 4. OCH₂CO₂H H H H CH₃ 5. OCH₂CH₂—CO₂CH₂CH₃ H H H H 6. OCH₂CH₂—CO₂CH₂CH₃ H H H CH₃ 7. OCH₂CH₂—CO₂H H H H H 8. OCH₂CH₂—CO₂H H H H CH₃ 9. OCH₂CH═CH—CO₂CH₂CH₃ H H H H 10. OCH₂CH═CH—CO₂CH₂CH₃ H H H CH₃ 11. OCH₂CH═CH—CO₂H H H H H 12. OCH₂CH═CH—CO₂H H H H CH₃ 13. OCH₂CH₂—PO(OCH₂CH₃)₂ H H H H 14. OCH₂CH₂—PO(OCH₂CH₃)₂ H H H CH₃ 15. OCH₂CH₂—PO(OH)₂ H H H H 16. OCH₂CH₂—PO(OH)₂ H H H CH₃ 17. H OCH₂CO₂—CH₂CH₃ H H H 18. H OCH₂CO₂—CH₂CH₃ H H CH₃ 19. H OCH₂CO₂H H H H 20. H OCH₂CO₂H H H CH₃ 21. H OCH₂CH₂CO₂—CH₂CH₃ H H H 22. H OCH₂CH₂CO₂—CH₂CH₃ H H CH₃ 23. H OCH₂CH₂CO₂H H H H 24. H OCH₂CH₂CO₂H H H CH₃ 25. H OCH₂CH═CH—CO₂CH₂CH₃ H H H 26. H OCH₂CH═CH—CO₂CH₂CH₃ H H CH₃ 27. H OCH₂CH═CH—CO₂H H H H 28. H OCH₂CH═CH—CO₂H H H CH₃ 29. H OCH₂CH₂—PO(OCH₂CH₃)₂ H H H 30. H OCH₂CH₂—PO(OCH₂CH₃)₂ H H CH₃ 31. H OCH₂CH₂—PO(OH)₂ H H H 32. H OCH₂CH₂—PO(OH)₂ H H CH₃ 33. H H OCH₂CO₂—CH₂CH₃ H H 34. H H OCH₂CO₂—CH₂CH₃ H CH₃ 35. H H OCH₂CO₂H H H 36. H H OCH₂CO₂H H CH₃ 37. H H OCH₂CH₂—CO₂CH₂CH₃ H H 38. H H OCH₂CH₂—CO₂CH₂CH₃ H CH₃ 39. H H OCH₂CH₂—CO₂H H H 40. H H OCH₂CH₂—CO₂H H CH₃ 41. H H OCH₂—CH═CH—CO₂CH₂CH₃ H H 42. H H OCH₂—CH═CH—CO₂CH₂CH₃ H CH₃ 43. H H OCH₂—CH═CHCO₂H H H 44. H H OCH₂—CH═CHCO₂H H CH₃ 45. H H OCH₂CH₂PO—(OCH₂CH₃)₂ H H 46. H H OCH₂CH₂PO—(OCH₂CH₃)₂ H CH₃ 47. H H OCH₂CH₂—PO(OH)₂ H H 48. H H OCH₂CH₂—PO(OH)₂ H CH₃ 49. H H H OCH₂CO₂—CH₂CH₃ H 50. H H H OCH₂CO₂—CH₂CH₃ CH₃ 51. H H H OCH₂CO₂H H 52. H H H OCH₂CO₂H CH₃ 53. H H H OCH₂CH₂—CO₂CH₂CH₃ H 54. H H H OCH₂CH₂—CO₂CH₂CH₃ CH₃ 55. H H H OCH₂CH₂—CO₂H H 56. H H H OCH₂CH₂—CO₂H CH₃ 57. H H H OCH₂—CH═CH—CO₂CH₂CH₃ H 58. H H H OCH₂—CH═CH—CO₂CH₂CH₃ CH₃ 59. H H H OCH₂—CH═CHCO₂H H 60. H H H OCH₂—CH═CHCO₂H CH₃ 61. H H H OCH₂CH₂PO—(OCH₂CH₃)₂ H 62. H H H OCH₂CH₂PO—(OCH₂CH₃)₂ CH₃ 63. H H H OCH₂CH₂—PO(OH)₂ H 64. H H H OCH₂CH₂—PO(OH)₂ CH₃

TABLE Vb

Ex. # X X¹ X² X³ R¹ 1. OCH₂CO₂—CH₂CH₃ H H H H 2. OCH₂CO₂—CH₂CH₃ H H H CH₃ 3. OCH₂CO₂H H H H H 4. OCH₂CO₂H H H H CH₃ 5. OCH₂CH₂—CO₂CH₂CH₃ H H H H 6. OCH₂CH₂—CO₂CH₂CH₃ H H H CH₃ 7. OCH₂CH₂—CO₂H H H H H 8. OCH₂CH₂—CO₂H H H H CH₃ 9. OCH₂CH═CH—CO₂CH₂CH₃ H H H H 10. OCH₂CH═CH—CO₂CH₂CH₃ H H H CH₃ 11. OCH₂CH═CH—CO₂H H H H H 12. OCH₂CH═CH—CO₂H H H H CH₃ 13. OCH₂CH₂—PO(OCH₂CH₃)₂ H H H H 14. OCH₂CH₂—PO(OCH₂CH₃)₂ H H H CH₃ 15. OCH₂CH₂—PO(OH)₂ H H H H 16. OCH₂CH₂—PO(OH)₂ H H H CH₃ 17. H OCH₂CO₂—CH₂CH₃ H H H 18. H OCH₂CO₂—CH₂CH₃ H H CH₃ 19. H OCH₂CO₂H H H H 20. H OCH₂CO₂H H H CH₃ 21. H OCH₂CH₂CO₂—CH₂CH₃ H H H 22. H OCH₂CH₂CO₂—CH₂CH₃ H H CH₃ 23. H OCH₂CH₂CO₂H H H H 24. H OCH₂CH₂CO₂H H H CH₃ 25. H OCH₂CH═CH—CO₂CH₂CH₃ H H H 26. H OCH₂CH═CH—CO₂CH₂CH₃ H H CH₃ 27. H OCH₂CH═CH—CO₂H H H H 28. H OCH₂CH═CH—CO₂H H H CH₃ 29. H OCH₂CH₂—PO(OCH₂CH₃)₂ H H H 30. H OCH₂CH₂—PO(OCH₂CH₃)₂ H H CH₃ 31. H OCH₂CH₂—PO(OH)₂ H H H 32. H OCH₂CH₂—PO(OH)₂ H H CH₃ 33. H H OCH₂CO₂—CH₂CH₃ H H 34. H H OCH₂CO₂—CH₂CH₃ H CH₃ 35. H H OCH₂CO₂H H H 36. H H OCH₂CO₂H H CH₃ 37. H H OCH₂CH₂—CO₂CH₂CH₃ H H 38. H H OCH₂CH₂—CO₂CH₂CH₃ H CH₃ 39. H H OCH₂CH₂—CO₂H H H 40. H H OCH₂CH₂—CO₂H H CH₃ 41. H H OCH₂—CH═CH—CO₂CH₂CH₃ H H 42. H H OCH₂—CH═CH—CO₂CH₂CH₃ H CH₃ 43. H H OCH₂—CH═CHCO₂H H H 44. H H OCH₂—CH═CHCO₂H H CH₃ 45. H H OCH₂CH₂PO—(OCH₂CH₃)₂ H H 46. H H OCH₂CH₂PO—(OCH₂CH₃)₂ H CH₃ 47. H H OCH₂CH₂—PO(OH)₂ H H 48. H H OCH₂CH₂—PO(OH)₂ H CH₃ 49. H H H OCH₂CO₂—CH₂CH₃ H 50. H H H OCH₂CO₂—CH₂CH₃ CH₃ 51. H H H OCH₂CO₂H H 52. H H H OCH₂CO₂H CH₃ 53. H H H OCH₂CH₂—CO₂CH₂CH₃ H 54. H H H OCH₂CH₂—CO₂CH₂CH₃ CH₃ 55. H H H OCH₂CH₂—CO₂H H 56. H H H OCH₂CH₂—CO₂H CH₃ 57. H H H OCH₂—CH═CH—CO₂CH₂CH₃ H 58. H H H OCH₂—CH═CH—CO₂CH₂CH₃ CH₃ 59. H H H OCH₂—CH═CHCO₂H H 60. H H H OCH₂—CH═CHCO₂H CH₃ 61. H H H OCH₂CH₂PO—(OCH₂CH₃)₂ H 62. H H H OCH₂CH₂PO—(OCH₂CH₃)₂ CH₃ 63. H H H OCH₂CH₂—PO(OH)₂ H 64. H H H OCH₂CH₂—PO(OH)₂ CH₃

TABLE VIa

Ex. # X X¹ X² R A⁻ 1. H H H CH₃ Cl⁻ 2. H H H CH₂C≡CH Cl⁻ 3. H OCH₃ H CH₃ Cl⁻ 4. H OCH₃ H CH₂C≡CH Cl⁻ 5. H H OCH₃ CH₃ Cl⁻ 6. H H OCH₃ CH₂C≡CH Cl⁻ 7. OCH₃ H H CH₃ Cl⁻ 8. OCH₃ H H CH₂C≡CH Cl⁻ 9. H OCH₂C₆H₅ H CH₃ Cl⁻ 10. H OCH₂C₆H₅ H CH₂C≡CH Cl⁻ 11. H H OCH₂C₆H₅ CH₃ Cl⁻ 12. H H OCH₂C₆H₅ CH₂C≡CH Cl⁻ 13. OCH₂C₆H₅ H H CH₃ Cl⁻ 14. OCH₂C₆H₅ H H CH₂C≡CH Cl⁻ 15. H Cl H CH₃ Cl⁻ 16. H Cl H CH₂C≡CH Cl⁻ 17. H H Cl CH₃ Cl⁻ 18. H H Cl CH₂C≡CH Cl⁻ 19. Cl H H CH₃ Cl⁻ 20. Cl H H CH₂C≡CH Cl⁻ 21. H OH H CH₃ Cl⁻ 22. H OH H CH₂C≡CH Cl⁻ 23. H H OH CH₃ Cl⁻ 24. H H OH CH₂C≡CH Cl⁻ 25. OH H H CH₃ Cl⁻ 26. OH H H CH₂C≡CH Cl⁻ 27. H OCH₂CH═CH₂ H CH₃ Cl⁻ 28. H OCH₂CH═CH₂ H CH₂C≡CH Cl⁻ 29. H H OCH₂CH═CH₂ CH₃ Cl⁻ 30. H H OCH₂CH═CH₂ CH₂C≡CH Cl⁻ 31. OCH₂CH═CH₂ H H CH₃ Cl⁻ 32. OCH₂CH═CH₂ H H CH₂C≡CH Cl⁻ 33. H NO₂ H CH₃ Cl⁻ 34. H NO₂ H CH₂C≡CH Cl⁻ 35. H H NO₂ CH₃ Cl⁻ 36. H H NO₂ CH₂C≡CH Cl⁻ 37. NO₂ H H CH₃ Cl⁻ 38. NO₂ H H CH₂C≡CH Cl⁻ 39. H NHSO₂CH₃ H CH₃ Cl⁻ 40. H NHSO₂CH₃ H CH₂C≡CH Cl⁻ 41. H H NHSO₂CH₃ CH₃ Cl⁻ 42. H H NHSO₂CH₃ CH₂C≡CH Cl⁻ 43. NHSO₂CH₃ H H CH₃ Cl⁻ 44. NHSO₂CH₃ H H CH₂C≡CH Cl⁻ 45. H H OCH₂CONH₂ CH₃ Cl⁻ 46. H H OCH₂CONH₂ CH₂C≡CH Cl⁻ 47. H OCH₂CONH₂ H CH₃ Cl⁻ 48. H OCH₂CONH₂ H CH₂C≡CH Cl⁻ 49. OCH₂CONH₂ H H CH₃ Cl⁻ 50. OCH₂CONH₂ H H CH₂C≡CH Cl⁻ 51. H OCH₂CH₂C₆H₅ H CH₃ Cl⁻ 52. H OCH₂CH₂C₆H₅ H CH₂C≡CH Cl⁻ 53. H H OCH₂CH₂C₆H₅ CH₃ Cl⁻ 54. H H OCH₂CH₂C₆H₅ CH₂C≡CH Cl 55. OCH₂CH₂C₆H₅ H H CH₃ Cl 56. OCH₂CH₂C₆H₅ H H CH₂C≡CH Cl 57. H OCH₂C₆H₄—Cl(3) H CH₃ Cl 58. H OCH₂C₆H₄—Cl(3) H CH₂C≡CH Cl 59. H H OCH₂C₆H₄—Cl(3) CH₃ Cl 60. H H OCH₂C₆H₄—Cl(3) CH₂C≡CH Cl 61. OCH₂C₆H₄—Cl(3) H H CH₃ Cl 62. OCH₂C₆H₄—Cl(3) H H CH₂C≡CH Cl 63. H OCH₂C₆H₄—Cl(4) H CH₃ Cl 64. H OCH₂C₆H₄—Cl(4) H CH₂C≡CH Cl 65. H H OCH₂C₆H₄—Cl(4) CH₃ Cl 66. H H OCH₂C₆H₄—Cl(4) CH₂C≡CH Cl 67. OCH₂C₆H₄—Cl(4) H H CH₃ Cl 68. OCH₂C₆H₄—Cl(4) H H CH₂C≡CH Cl 69. H OCH₂C₆H₄CF₃(3) H CH₃ Cl 70. H OCH₂C₆H₄CF₃(3) H CH₂C≡CH Cl 71. OCH₂C₆H₄CF₃(3) H H CH₃ Cl 72. OCH₂C₆H₄CF₃(3) H H CH₂C≡CH Cl 73. H H OCH₂C₆H₄CF₃(3) CH₃ Cl 74. H H OCH₂C₆H₄CF₃(3) CH₂C≡CH Cl 75. H OCH₂C₆H₄CF₃(4) H CH₃ Cl 76. H OCH₂C₆H₄CF₃(4) H CH₂C≡CH Cl 77. OCH₂C₆H₄CF₃(4) H H CH₃ Cl 78. OCH₂C₆H₄CF₃(4) H H CH₂C≡CH Cl 79. H H OCH₂C₆H₄CF₃(4) CH₃ Cl 80. H H OCH₂C₆H₄CF₃(4) CH₂C≡CH Cl

TABLE VIb

Ex. # X X¹ X² R¹ 1. H H H H 2. H H H CH₃ 3. H OCH₃ H H 4. H OCH₃ H CH₃ 5. H H OCH₃ H 6. H H OCH₃ CH₃ 7. OCH₃ H H H 8. OCH₃ H H CH₃ 9. H OCH₂C₆H₅ H H 10. H OCH₂C₆H₅ H CH₃ 11. H H OCH₂C₆H₅ H 12. H H OCH₂C₆H₅ CH₃ 13. OCH₂C₆H₅ H H H 14. OCH₂C₆H₅ H H CH₃ 15. H Cl H H 16. H Cl H CH₃ 17. H H Cl H 18. H H Cl CH₃ 19. Cl H H H 20. Cl H H CH₃ 21. H OH H H 22. H OH H CH₃ 23. H H OH H 24. H H OH CH₃ 25. OH H H H 26. OH H H CH₃ 27. H OHC₂CH═CH₂ H H 28. H OHC₂CH═CH₂ H CH₃ 29. H H OHC₂CH═CH₂ H 30. H H OHC₂CH═CH₂ CH₃ 31. OHC₂CH═CH₂ H H H 32. OHC₂CH═CH₂ H H CH₃ 33. H NO₂ H H 34. H NO₂ H CH₃ 35. H H NO₂ H 36. H H NO₂ CH₃ 37. NO₂ H H H 38. NO₂ H H CH₃ 39. H NHSO₂CH₃ H H 40. H NHSO₂CH₃ H CH₃ 41. H H NHSO₂CH₃ H 42. H H NHSO₂CH₃ CH₃ 43. NHSO₂CH₃ H H H 44. NHSO₂CH₃ H H CH₃ 45. H H OCH₂CONH₂ H 46. H H OCH₂CONH₂ CH₃ 47. H OCH₂CONH₂ H H 48. H OCH₂CONH₂ H CH₃ 49. OCH₂CONH₂ H H H 50. OCH₂CONH₂ H H CH₃ 51. H OCH₂CH₂C₆H₅ H H 52. H OCH₂CH₂C₆H₅ H CH₃ 53. H H OCH₂CH₂C₆H₅ H 54. H H OCH₂CH₂C₆H₅ CH₃ 55. OCH₂CH₂C₆H₅ H H H 56. OCH₂CH₂C₆H₅ H H CH₃ 57. H OCH₂C₆H₄—Cl(3) H H 58. H OCH₂C₆H₄—Cl(3) H CH₃ 59. H H OCH₂C₆H₄—Cl(3) H 60. H H OCH₂C₆H₄—Cl(3) CH₃ 61. OCH₂C₆H₄—Cl(3) H H H 62. OCH₂C₆H₄—Cl(3) H H CH₃ 63. H OCH₂C₆H₄—Cl(4) H H 64. H OCH₂C₆H₄—Cl(4) H CH₃ 65. H H OCH₂C₆H₄—Cl(4) CH₃ 66. H H OCH₂C₆H₄—Cl(4) H 67. OCH₂C₆H₄—Cl(4) H H CH₃ 68. OCH₂C₆H₄—Cl(4) H H H 69. H OCH₂C₆H₄CF₃(3) H H 70. H OCH₂C₆H₄CF₃(3) H CH₃ 71. OCH₂C₆H₄CF₃(3) H H H 72. OCH₂C₆H₄CF₃(3) H H CH₃ 73. H H OCH₂C₆H₄CF₃(3) H 74. H H OCH₂C₆H₄CF₃(3) CH₃ 75. H OCH₂C₆H₄CF₃(4) H H 76. H OCH₂C₆H₄CF₃(4) H CH₃ 77. OCH₂C₆H₄CF₃(4) H H H 78. OCH₂C₆H₄CF₃(4) H H CH₃ 79. H H OCH₂C₆H₄CF₃(4) H 80. H H OCH₂C₆H₄CF₃(4) CH₃

TABLE VIIa

Ex. # X X¹ X² R 1. OCH₂CH═CH₂ H H H 2. OCH₂CH═CH₂ H H CH₃ 3. CF₃ H H H 4. CF₃ H H CH₃ 5. NO₂ H H H 6. NO₂ H H CH₃ 7. CH₃ H H H 8. CH₃ H H CH₃ 9. NHSO₂CH₃ H H H 10. NHSO₂CH₃ H H CH₃ 11. OCH₂C₆H₅ H H H 12. OCH₂C₆H₅ H H CH₃ 13. OCH₂C₆H₄—Cl(3) H H H 14. OCH₂C₆H₄—Cl(3) H H CH₃ 15. OCH₂C₆H₄—Cl(4) H H H 16. OCH₂C₆H₄—Cl(4) H H CH₃ 17. OCH₂C₆H₄—F(3) H H H 18. OCH₂C₆H₄—F(3) H H CH₃ 19. OCH₂C₆H₄—F(4) H H H 20. OCH₂C₆H₄—F(4) H H CH₃ 21. OCH₂C₆H₄—CF₃ (3) H H H 22. OCH₂C₆H₄—CF₃ (3) H H CH₃ 23. OCH₂C₆H₄—CF₃(4) H H H 24. OCH₂C₆H₄—CF₃(4) H H CH₃ 25. OCH₂C₆H₄—NO₂ (3) H H H 26. OCH₂C₆H₄—NO₂ (3) H H CH₃ 27. OCH₂C₆H₄—NO₂ (4) H H H 28. OCH₂C₆H₄—NO₂ (4) H H CH₃ 29. OCH₂C₆H₄—NHSO₂CH₃ (3) H H H 30. OCH₂C₆H₄—NHSO₂CH₃ (3) H H CH₃ 31. OCH₂C₆H₄—NHSO₂CH₃ (4) H H H 32. OCH₂C₆H₄—NHSO₂CH₃ (4) H H CH₃ 33. OCH₂C₆H₄—CN(3) H H H 34. OCH₂C₆H₄—CN(3) H H CH₃ 35. OCH₂C₆H₄—CN(4) H H H 36. OCH₂C₆H₄—CN(4) H H CH₃ 37. OCH₂C₆H₄—CONH₂(3) H H H 38. OCH₂C₆H₄—CONH₂(3) H H CH₃ 39. OCH₂C₆H₄—CONH₂(4) H H H 40. OCH₂C₆H₄—CONH₂(4) H H CH₃ 41. OCH₂C₆H₄—CH₂CN(3) H H H 42. OCH₂C₆H₄—CH₂CN(3) H H CH₃ 43. OCH₂C₆H₄—CH₂CN(4) H H H 44. OCH₂C₆H₄—CH₂CN(4) H H CH₃ 45. OCH₂C₆H₄—CH₂CONH₂(3) H H H 46. OCH₂C₆H₄—CH₂CONH₂(3) H H CH₃ 47. OCH₂C₆H₄—CH₂CONH₂(4) H H H 48. OCH₂C₆H₄—CH₂CONH₂(4) H H CH₃ 49. OCH₂C₆H₄—OCH₂CN(3) H H H 50. OCH₂C₆H₄—OCH₂CN(3) H H CH₃ 51. OCH₂C₆H₄—OCH₂CN(4) H H H 52. OCH₂C₆H₄—OCH₂CN(4) H H CH₃ 53. OCH₂C₆H₄—OCH₂CONH₂(3) H H H 54. OCH₂C₆H₄—OCH₂CONH₂(3) H H CH₃ 55. OCH₂C₆H₄—OCH₂CONH₂(4) H H H 56. OCH₂C₆H₄—OCH₂CONH₂(4) H H CH₃ 57. OCH₂C₆H₃—(CN)₂(3,5) H H H 58. OCH₂C₆H₃—(CN)₂(3,5) H H CH₃ 59. OCH₂C₆H₃—(CN)₂(3,5) H H H 60. OCH₂C₆H₃—(CN)₂(3,5) H H CH₃ 61. OCH₂C₆H₃—(CONH₂)₂(3,5) H H H 62. OCH₂C₆H₃—(CONH₂)₂(3,5) H H CH₃ 63. OCH₂C₆H₃—(CONH₂)₂(3,5) H H H 64. OCH₂C₆H₃—(CONH₂)₂(3,5) H H CH₃ 65. OCH₂CH₂C₆H₅ H H H 66. OCH₂CH₂C₆H₅ H H CH₃ 67. OCH₂C₆H₄C₆H₄CN(2) H H H 68. OCH₂C₆H₄C₆H₄CN(2) H H CH₃ 69. OCH₂C₆H₄C₆H₄CONH₂(2) H H H 70. OCH₂C₆H₄C₆H₄CONH₂(2) H H CH₃

TABLE VIIb

Ex. # X¹ X X² R 1. OHC₂CH═CH₂ H H H 2. OHC₂CH═CH₂ H H CH₃ 3. CF₃ H H H 4. CF₃ H H CH₃ 5. NO₂ H H H 6. NO₂ H H CH₃ 7. CH₃ H H H 8. CH₃ H H CH₃ 9. NHSO₂CH₃ H H H 10. NHSO₂CH₃ H H CH₃ 11. OCH₂C₆H₅ H H H 12. OCH₂C₆H₅ H H CH₃ 13. OCH₂C₆H₄—Cl(3) H H H 14. OCH₂C₆H₄—Cl(3) H H CH₃ 15. OCH₂C₆H₄—Cl(4) H H H 16. OCH₂C₆H₄—Cl(4) H H CH₃ 17. OCH₂C₆H₄—F(3) H H H 18. OCH₂C₆H₄—F(3) H H CH₃ 19. OCH₂C₆H₄—F(4) H H H 20. OCH₂C₆H₄—F(4) H H CH₃ 21. OCH₂C₆H₄—CF₃ (3) H H H 22. OCH₂C₆H₄—CF₃ (3) H H CH₃ 23. OCH₂C₆H₄—CF₃(4) H H H 24. OCH₂C₆H₄—CF₃(4) H H CH₃ 25. OCH₂C₆H₄—NO₂ (3) H H H 26. OCH₂C₆H₄—NO₂ (3) H H CH₃ 27. OCH₂C₆H₄—NO₂ (4) H H H 28. OCH₂C₆H₄—NO₂ (4) H H CH₃ 29. OCH₂C₆H₄—NHSO₂CH₃ (3) H H H 30. OCH₂C₆H₄—NHSO₂CH₃ (3) H H CH₃ 31. OCH₂C₆H₄—NHSO₂CH₃ (4) H H H 32. OCH₂C₆H₄—NHSO₂CH₃ (4) H H CH₃ 33. OCH₂C₆H₄—CN(3) H H H 34. OCH₂C₆H₄—CN(3) H H CH₃ 35. OCH₂C₆H₄—CN(4) H H H 36. OCH₂C₆H₄—CN(4) H H CH₃ 37. OCH₂C₆H₄—CONH₂(3) H H H 38. OCH₂C₆H₄—CONH₂(3) H H CH₃ 39. OCH₂C₆H₄—CONH₂(4) H H H 40. OCH₂C₆H₄—CONH₂(4) H H CH₃ 41. OCH₂C₆H₄—CH₂CN(3) H H H 42. OCH₂C₆H₄—CH₂CN(3) H H CH₃ 43. OCH₂C₆H₄—CH₂CN(4) H H H 44. OCH₂C₆H₄—CH₂CN(4) H H CH₃ 45. OCH₂C₆H₄—CH₂CONH₂(3) H H H 46. OCH₂C₆H₄—CH₂CONH₂(3) H H CH₃ 47. OCH₂C₆H₄—CH₂CONH₂(4) H H H 48. OCH₂C₆H₄—CH₂CONH₂(4) H H CH₃ 49. OCH₂C₆H₄—OCH₂CN(3) H H H 50. OCH₂C₆H₄—OCH₂CN(3) H H CH₃ 51. OCH₂C₆H₄—OCH₂CN(4) H H H 52. OCH₂C₆H₄—OCH₂CN(4) H H CH₃ 53. OCH₂C₆H₄—OCH₂CONH₂(3) H H H 54. OCH₂C₆H₄—OCH₂CONH₂(3) H H CH₃ 55. OCH₂C₆H₄—OCH₂CONH₂(4) H H H 56. OCH₂C₆H₄—OCH₂CONH₂(4) H H CH₃ 57. OCH₂C₆H₃—(CN)₂(3,5) H H H 58. OCH₂C₆H₃—(CN)₂(3,5) H H CH₃ 59. OCH₂C₆H₃—(CN)₂(3,5) H H H 60. OCH₂C₆H₃—(CN)₂(3,5) H H CH₃ 61. OCH₂C₆H₃—(CONH₂)₂(3,5) H H H 62. OCH₂C₆H₃—(CONH₂)₂(3,5) H H CH₃ 63. OCH₂C₆H₃—(CONH₂)₂(3,5) H H H 64. OCH₂C₆H₃—(CONH₂)₂(3,5) H H CH₃ 65. OCH₂CH₂C₆H₅ H H H 66. OCH₂CH₂C₆H₅ H H CH₃ 67. OCH₂C₆H₄C₆H₄CN(2) H H H 68. OCH₂C₆H₄C₆H₄CN(2) H H CH₃ 69. OCH₂C₆H₄C₆H₄CONH₂(2) H H H 70. OCH₂C₆H₄C₆H₄CONH₂(2) H H CH₃

TABLE VIIc

Ex. # X² X X¹ R 1. OHC₂CH═CH₂ H H H 2. OHC₂CH═CH₂ H H CH₃ 3. CF₃ H H H 4. CF₃ H H CH₃ 5. NO₂ H H H 6. NO₂ H H CH₃ 7. CH₃ H H H 8. CH₃ H H CH₃ 9. NHSO₂CH₃ H H H 10. NHSO₂CH₃ H H CH₃ 11. OCH₂C₆H₅ H H H 12. OCH₂C₆H₅ H H CH₃ 13. OCH₂C₆H₄—Cl(3) H H H 14. OCH₂C₆H₄—Cl(3) H H CH₃ 15. OCH₂C₆H₄—Cl(4) H H H 16. OCH₂C₆H₄—Cl(4) H H CH₃ 17. OCH₂C₆H₄—F(3) H H H 18. OCH₂C₆H₄—F(3) H H CH₃ 19. OCH₂C₆H₄—F(4) H H H 20. OCH₂C₆H₄—F(4) H H CH₃ 21. OCH₂C₆H₄—CF₃ (3) H H H 22. OCH₂C₆H₄—CF₃ (3) H H CH₃ 23. OCH₂C₆H₄—CF₃(4) H H H 24. OCH₂C₆H₄—CF₃(4) H H CH₃ 25. OCH₂C₆H₄—NO₂ (3) H H H 26. OCH₂C₆H₄—NO₂ (3) H H CH₃ 27. OCH₂C₆H₄—NO₂ (4) H H H 28. OCH₂C₆H₄—NO₂ (4) H H CH₃ 29. OCH₂C₆H₄—NHSO₂CH₃ (3) H H H 30. OCH₂C₆H₄—NHSO₂CH₃ (3) H H CH₃ 31. OCH₂C₆H₄—NHSO₂CH₃ (4) H H H 32. OCH₂C₆H₄—NHSO₂CH₃ (4) H H CH₃ 33. OCH₂C₆H₄—CN(3) H H H 34. OCH₂C₆H₄—CN(3) H H CH₃ 35. OCH₂C₆H₄—CN(4) H H H 36. OCH₂C₆H₄—CN(4) H H CH₃ 37. OCH₂C₆H₄—CONH₂(3) H H H 38. OCH₂C₆H₄—CONH₂(3) H H CH₃ 39. OCH₂C₆H₄—CONH₂(4) H H H 40. OCH₂C₆H₄—CONH₂(4) H H CH₃ 41. OCH₂C₆H₄—CH₂CN(3) H H H 42. OCH₂C₆H₄—CH₂CN(3) H H CH₃ 43. OCH₂C₆H₄—CH₂CN(4) H H H 44. OCH₂C₆H₄—CH₂CN(4) H H CH₃ 45. OCH₂C₆H₄—CH₂CONH₂(3) H H H 46. OCH₂C₆H₄—CH₂CONH₂(3) H H CH₃ 47. OCH₂C₆H₄—CH₂CONH₂(4) H H H 48. OCH₂C₆H₄—CH₂CONH₂(4) H H CH₃ 49. OCH₂C₆H₄—OCH₂CN(3) H H H 50. OCH₂C₆H₄—OCH₂CN(3) H H CH₃ 51. OCH₂C₆H₄—OCH₂CN(4) H H H 52. OCH₂C₆H₄—OCH₂CN(4) H H CH₃ 53. OCH₂C₆H₄—OCH₂CONH₂(3) H H H 54. OCH₂C₆H₄—OCH₂CONH₂(3) H H CH₃ 55. OCH₂C₆H₄—OCH₂CONH₂(4) H H H 56. OCH₂C₆H₄—OCH₂CONH₂(4) H H CH₃ 57. OCH₂C₆H₃—(CN)₂(3,5) H H H 58. OCH₂C₆H₃—(CN)₂(3,5) H H CH₃ 59. OCH₂C₆H₃—(CN)₂(3,5) H H H 60. OCH₂C₆H₃—(CN)₂(3,5) H H CH₃ 61. OCH₂C₆H₃—(CONH₂)₂(3,5) H H H 62. OCH₂C₆H₃—(CONH₂)₂(3,5) H H CH₃ 63. OCH₂C₆H₃—(CONH₂)₂(3,5) H H H 64. OCH₂C₆H₃—(CONH₂)₂(3,5) H H CH₃ 65. OCH₂CH₂C₆H₅ H H H 66. OCH₂CH₂C₆H₅ H H CH₃ 67. OCH₂C₆H₄C₆H₄CN(2) H H H 68. OCH₂C₆H₄C₆H₄CN(2) H H CH₃ 69. OCH₂C₆H₄C₆H₄CONH₂(2) H H H 70. OCH₂C₆H₄C₆H₄CONH₂(2) H H CH₃

Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

1. A compound of formula I or II, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: R, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R¹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(m)CO₂R, C₂₋₆ alkenyl-CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, and, (CH₂)_(n)PO(OR)₂; A⁻ is a counter ion; V is selected from O⁻, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; X, X¹, X², and X³ are independently selected from H, OR, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, N(R)₂, (CH₂)_(m)-tetrazole, (CH₂)_(n)CO₂R, (CH₂)_(n)CONR₂, (CH₂)_(n)CN, O(CH₂)_(n)CN, O(CH₂)_(n)-tetrazole, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)PO(OR)₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)CON(R)₂, NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)SO₂OR, NR(CH₂)_(n)-tetrazole, SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, CH₂-aryl, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃A⁻, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n) heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴ and tetrazole is substituted with 0-1 R; X⁴ is selected from H, OR, O—C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl; Q is selected from H, OH, C₁₋₆ alkoxy, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₆ alkenyl, O—C₂₋₆ alkenyl-CO₂R, OCH₂CH₂CONRCH₂CO₂R, OCH₂CHMCONRCH₂CO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂CH(NHAc)CO₂R, OCH₂CH(NHR)CO₂R, O(CH₂)_(n)-aryl, and O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; W is selected from H, CO₂R, CON(R)₂, CH₂OH, CH₂OC₁₋₆ alkyl, CH₂OC₂₋₆ alkenyl, CH₂O(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)CON(R)₂, CH₂O—C₂₋₆ alkenyl-CO₂R, CH₂OCH₂CH₂CONRCH₂CO₂R, CH₂OCH₂CHMCONRCH₂CO₂R, CH₂O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)SO₂OR, CH₂OCH₂CH(NHAc)CO₂R, CH₂OCH₂CH(NHR)CO₂R, CH₂O—C₂₋₆ alkenyl, and CH₂O(CH₂)_(n)CONH₂, CH₂O(CH₂)_(n)-aryl, and CH₂O(CH₂)_(n)-5-12 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein heteroaryl is substituted with 1-2 X⁴; M is independently selected from H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, (CH₂)_(n)-aryl, heteroaryl, and (CH₂)_(n)-heteroaryl, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; m is independently selected from 0, 1, 2, 3, and 4; and, n is independently selected from 1, 2, 3, and 4; provided that at least one of X, X¹, X², and X³ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 2. A compound of claim 1, wherein the compound is of formula I₁ or II₁, or a stereoisomer or pharmaceutically acceptable salt thereof:


3. A compound of claim 1, wherein the compound is of formula Ia, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: R, at each occurrence, is independently selected from H and C₁₋₄ alkyl; R¹ is selected from H and C₁₋₄ alkyl; X and X¹ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, and NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; X⁴ is selected from H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl; n is independently selected from 1, 2, and 3; provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 4. A compound of claim 3, wherein: one of X and X¹ is H and the other is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, and NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 5. A compound of claim 3, wherein the compound is of formula Ia₁, or a stereoisomer or pharmaceutically acceptable salt thereof:


6. A compound of claim 1, wherein the compound is of formula Ib, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: R, at each occurrence, is independently selected from H and C₁₋₄ alkyl; R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(m)CO₂R, C₂₋₄ alkenyl-CO₂R, CH₂CH(NHAc)CO₂R, CH₂CH(NHR)CO₂R, and, (CH₂)_(n)PO(OR)₂; X and X¹ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; X⁴ is selected from H, OH, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl; W is selected from H, CH₂OH, CH₂OC₁₋₄ alkyl, CH₂OC₂₋₄ alkenyl, CH₂O(CH₂)_(n)CO₂R, CH₂O—C₂₋₄ alkenyl-CO₂R, CH₂O(CH₂)_(n)CON(R)₂, CH₂O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)-aryl, and CH₂O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; m is independently selected from 0, 1, and 2; and, n is independently selected from 1, 2, and 3; provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 7. A compound of claim 6, wherein: one of X and X¹ is H and the other is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 8. A compound of claim 6, wherein the compound is of formula Ib₁, or a stereoisomer or pharmaceutically acceptable salt thereof:


9. A compound of claim 1, wherein the compound is of formula Ic, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹ is selected from H and C₁₋₄ alkyl; X, X¹, X², and X³ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, N(R)₂, (CH₂)_(m)-tetrazole, (CH₂)_(n)CO₂R, (CH₂)_(n)CONR₂, (CH₂)_(n)CN, O(CH₂)_(n)CN, O(CH₂)_(n)-tetrazole, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)PO(OR)₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)CON(R)₂, NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)SO₂OR, NR(CH₂)_(n)-tetrazole, SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, CH₂-aryl, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃A⁻, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n) heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴ and tetrazole is substituted with 0-1 R; X⁴ is selected from H, OR, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl; A⁻ is selected from Cl and Br; M is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, heteroaryl, and (CH₂)_(n)-heteroaryl, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and, m is independently selected from 0, 1, and 2; and, n is independently selected from 1, 2, and 3; provided that at least one of X, X¹, X², and X³ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 10. A compound of claim 9, wherein: three of X, X¹, X², and X³ are H and the fourth is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, C₁₋₄ alkoxy, —CN, N(R)₂, (CH₂)_(m)-tetrazole, (CH₂)_(n)CO₂R, (CH₂)_(n)CONR₂, (CH₂)_(n)CN, O(CH₂)_(n)CN, O(CH₂)_(n)-tetrazole, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)PO(OR)₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)CON(R)₂, NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)SO₂OR, NR(CH₂)_(n)-tetrazole, SO₂NRCH₃, OCH₂CHMCONRCH₂CO₂R, CH₂-aryl, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂(CH₂)_(n)N⁺(CH₃)₃A⁻, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n) heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₄ alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, where heteroaryl is a 5-10 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴ and tetrazole is substituted with 0-1 R; provided that at least one of X, X¹, X², and X³ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 11. A compound of claim 9, wherein the compound is of formula Ic₁, or a stereoisomer or pharmaceutically acceptable salt thereof:


12. A compound of claim 1, wherein the compound is of formula Id, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(m)CO₂R, (CH₂)_(n)PO(OR)₂, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; X, X¹, and X² are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; X⁴ is selected from H, OH, C₁₋₆ alkoxy C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl; Q is selected from OH, C₁₋₄ alkoxy, O(CH₂)_(n)CO₂R, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, O—C₂₋₄ alkenyl-CO₂R, OCH₂CH₂CONRCH₂CO₂R, OCH₂CHMCONRCH₂CO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)SO₂OR, OCH₂CH(NHAc)CO₂R, OCH₂CH(NHR)CO₂R, O(CH₂)_(n)-aryl, and O(CH₂)_(n)-5-10 membered heteroaryl consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; M is independently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, (CH₂)_(n)-aryl, heteroaryl, and (CH₂)_(n)-heteroaryl, where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S; and, m is independently selected from 0, 1, and 2; and, n is independently selected from 1, 2, and 3; provided that at least one of X, X¹, and X² is other than H, alkyl, alkoxy, hydroxyl, and halo.
 13. A compound of claim 12, wherein: two of X, X¹, and X² are H and the third is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, N(R)₂, NRSO₂CH₃, SO₂NRCH₃, CH₂N(C₁₋₄ alkyl)₂, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; provided that at least one of X, X¹, and X² is other than H, alkyl, alkoxy, hydroxyl, and halo.
 14. A compound of claim 12, wherein the compound is of formula Id₁, or a stereoisomer or pharmaceutically acceptable salt thereof:


15. A compound of claim 1, wherein the compound is of formula IIa, or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein: R, at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹ is selected from H and C₁₋₄ alkyl; A⁻ is selected from Cl⁻- and Br⁻; V is selected from O⁻, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; X and X¹ are independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, NRSO₂CH₃, SO₂NRCH₃, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; X⁴ is selected from H, OR, C₁₋₆ alkoxy C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, CF₃, nitro, —CN, C(O)NR₂, NRSO₂CH₃, and, SO₂N(R)C₁₋₆alkyl; n is independently selected from 1, 2, and 3; provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 16. A compound of claim 15, wherein: one of X and X¹ is H and the other is selected from OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, C₁₋₄ alkoxy, O(CH₂)_(n)CON(R)₂, O—C₂₋₄ alkenyl, NRSO₂CH₃, SO₂NRCH₃, CH₂-aryl, CH₂-heteroaryl, O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-CN, O(CH₂)_(n)-biphenyl-CONH₂, NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-CN, NR(CH₂)_(n)-biphenyl-CONH₂, O(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂, and NR(CH₂)_(n)-heteroaryl-(CH₂)_(m)CON(R)₂; where heteroaryl is a 5-12 membered ring system consisting of carbon atoms and from 1-4 heteroatoms selected from N, O, and S, and wherein aryl and heteroaryl are substituted with 1-2 X⁴; provided that at least one of X and X¹ is other than H, alkyl, alkoxy, hydroxyl, and halo.
 17. A compound of claim 15, wherein the compound is of formula IIa₁, or a stereoisomer or pharmaceutically acceptable salt thereof:


18. A compound selected from Table I, IIa, IIb, III, IV, Va, Vb, VIa, VIb, VIIa, VIIb, or VIIc or a pharmaceutically acceptable salt thereof.
 19. A pharmaceutical composition, comprising: a compound of claim 1 and a pharmaceutically acceptable carrier.
 20. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.
 21. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof, wherein the disease is a co-morbidty of obesity.
 22. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof, wherein the disease is a CNS disorder. 